OA12286A - 2-Aminothiazoline derivatives and their use as no-synthase inhibitors. - Google Patents

Abstract

The invention concerns 2-aminithiazoline derivatives of formula (I) wherein: either R1 is a hydrogen atom or an alkyl radical and R2 is an alkyl, -alk-NH2, -CH-R3, -CH2-S-R4 or phenyl radical substituted by a nitro or NH-C(=NH)CH3 radical; or R1 is an alkyl radical and R2 is a hydrogen atom; R3 is a cycloalkyl (3-6C), pyridyl, pyridyl N-oxide, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or phenyl radical substituted by a nitro, hydroxy or carboxy radical; R4 represents a pyridyl or pyridyl N-oxide radical; alk represents an alkylene radical or their pharmaceutically acceptable salts excluding some known compounds, and the use of said derivatives as inducible NO-synthase inhibitors.

Description

1 012286

2-AMINOTHIAZOLINE DERIVATIVES AND THEIR USE

AS INHIBITORS OF NO-SYNTHASE

The present invention relates to the use of 2-aminothiazoline derivatives of the formula: R. (0

or their pharmaceutically acceptable salts as NO-synthaseinducible inhibitors. The invention relates to the use of 2-aminothiazoline derivatives of formula (1) and their pharmaceutically acceptable salts for the preparation of pharmaceutical compositions for preventing and treating diseases in which abnormal production of nitric oxide (NO) by NO-synthaseinducible induction (NOS-2 or iNOS) is involved, the pharmaceutical compositions containing the novel 2-aminothiazoline derivatives and their pharmaceutically acceptable salts and the novel 2-aminothiazoline derivatives and their pharmaceutically acceptable salts.

Nitric oxide (NO) is a diffusible radical involved in many physiological and pathological processes. It is synthesized by oxidation of L-arginine, a reaction catalyzed by a family of enzymes called synthase nitrous oxide or NO-Synthase (NOS), referenced in the international system of nomenclature of enzymes under number EC 1.14.13.39 .

Three isoforms of NOS, two of which are constitutive and one inducible, are known: - a neuronal NOS (NOS-1 or nNOS) was isolated and cloned originally from the nervous tissue where it is a constitutive enzyme. NOS-1 produces NO in response to various physiological stimuli such as activation of membrane receptors by a calcium-dependent and calmodulin-dependent mechanism. an inducible NOS (NOS-2 or iNOS) can be induced in response to immunological stimuli such as, for example, cytokines or bacterial antigens in 5 different cells such as, for example, macrophages, endothelial cells, hepatocytes, glial cells , as well as a large number of other types of cells. The activity of this isoform is not regulated by calcium. This is why, once induced, it produces large quantities of NO over prolonged periods of time. an endothelial NOS (NOS-3 or eNOS) is constitutive and calcium / calmodulin dependent. It was originally identified in vascular endothelial cells where it generates NO in response to physiological stimuli such as activation of membrane receptors.

The NO produced by the constituent neuronal and endothelial isoforms (NOS-1 and NOS-3) is generally involved in intercellular signaling functions. For example, endothelial cells lining the inner lining of blood vessels cause relaxation of underlying smooth muscle cells via the production of NO. Π thus contributes to the regulation of blood pressure.

NO produced in large quantities by the inducible NOS-2 isoform is, among other things, involved in the pathological phenomena associated with acute and chronic inflammatory processes in a wide variety of tissues and organs.

Excessive production of NO by induction of NOS-2 thus participates in degenerative diseases of the nervous system such as, for example, multiple sclerosis, focal or global cerebral ischemia, cerebral or ouspinal traumas, Parkinson's disease, Huntington's disease, the disease. Alzheimer's disease, amyotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety, epilepsy. Likewise, outside the central nervous system, the induction of NOS-2 is involved in many pathologies with inflammatory components.

AT

012286 such as diabetes, atherosclerosis, myocarditis, arthritis, osteoarthritis, asthma, irritable bowel syndrome, Crohn's disease, peritonitis, gastroesophageal reflux, uveitis , Guillain-Barré syndrome, glomerulo- nephritis, lupus erythematosus, psoriasis. NOS-2 has also been implicated in the growth of some forms of tumors such as epitheliomas, adenocarcinomas or sarcomas, and in infections with intracellular or extracellular, Gram-plus or Gram-less bacteria.

In all situations where NO overproduction is harmful, it is therefore desirable to reduce NO production by the administration of substances capable of inhibiting NOS-2. However, in view of the important physiological roles played by the constitutive isoform NOS-3 particularly in the regulation of arterial pressure, it is essential that the inhibition of the NOS-2 isoform affects as little as possible the NOS-3 isoform. Indeed, it is known that administration of non-selective inhibitors of NOS isoforms leads to vasoconstriction and increased blood pressure (Moncada, S., Palmer, RMJ and Higgs, EA, Biosynthesis of nitric oxide from L Arginine: A Pathway for the Regulation of Cell Function and Communication, Biochem Pharmacol., 1989, 38: 1709-1715). These effects on the cardiovascular system are deleterious to the extent that they reduce nutrient supply to tissues. Therefore, the present invention relates to compounds having a significantly greater NOS-2 inhibitory activity than its NOS-3 inhibitory activity.

Inhibitors of NOS thiazoline derivatives are described in particular in patent applications WO94 / 12165, WO95 / 11231 and WO96 / 14842.

The present invention relates to the use of the 2-aminothiazoline derivatives of formula (I) in which: either R 1 is a hydrogen atom or an alkyl radical and R 2 is an alkyl radical, -alk-NEfe, -CH 2 -R 3 , -CH 2 -S-R 4 or phenyl substituted with a nitro radical or -NH-C (= NH) CH 3, wherein R 1 is an alkyl radical and R 2 is a hydrogen atom, R 3 is a cycloalkyl radical (3- 6C), pyridyl, pyridyl, phenyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or nitro substituted phenyl, hydroxy or carboxy, R4 represents a pyridyl radical or pyridyl N-oxide alk represents an alkylene radical for the preparation of medicaments useful for preventing or treating diseases in which abnormal production of nitric oxide (NO) by induction of inducible NO synthase (NOS-2 or iNOS) is involved. In the preceding definitions and those which follow, the alkyl and alkylenes contain 1 to 6 carbon atoms in straight or branched chain.

The compounds of formula (I) have one or more asymmetric carbons and can therefore be in the form of racemic, enantiomers and di-diastereoisomers; these are also part of the invention as well as their blends.

Moreover, the compounds of formula (1) can be in the formetautomère (la):

Rt * 2

(the)

These tautomers are also part of the invention. Among the compounds of formula (Γ) useful according to the invention, mention may be made of the following compounds: 4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4-benzyl-5-methyl, 5-dihydro-1,3-tiazol-2-ylamine 4- (3-thienylmethyl) -4, 5-Dihydro-1,3-thiazol-2-ylamine 4- (2-thienylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro) thiazol-4-yl) -phenyl] - (1-imino-ethyl) -amine 4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-carboxybenzyl) -4,5 4-Dihydro-1,3-thiazol-2-ylamine 4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine-4-butyl-4,5-dihydro-1,3-thiazol -2-ylamine-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine 4-cyclohexylmethyl-4,5-dihydro-1,3-tbiazol-2-ylamine 4- (3-nitropbenyl) -4,5-dibydro-1,3-thiazol-2-ylamine 4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine-5-methyl-4- (4-pyridylmethyl) -4,5-Dihydro-1,3-thiazol-2-ylamine 5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-triazol-2-ylamine 4- (4-th) ia2olylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylainine 4- (2-pyrazinylmethyl) -4 5-Dihydro-1,3-thiazol-2-ylamine 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-hydroxybenzyl) -4,5-dihydro 1,1,3-Thiazol-2-ylamine 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-aminopropyl) -4,5-dihydro-1, 4-(4-Pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-triazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamineN-oxide -thiazol-2-ylamine

Their racemic, enantiomeric, diastereoisomeric, tautomeric and pharmaceutically acceptable salts, and more particularly the following compounds: (+) - (4R) -4- (3-pyridylmethyl) -4,5-dihydro-1,3- thiazol-2-ylamine (+) - (4R) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5S) -4-benzyl- 5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine 6 (+) - (4R, 5R) -4-Benzyl-5-methyl-4,5-dihydro-1H-tiazol-2-ylamine (-) - (4R) -4- (3-Thienylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4R) -4- (2-tHenylmethyl) -4,5-dihydro -ylamine -1,3-Thiazol-2-ylamine [3- (2-amino-4,5-dihydro-thiazol-4-yl) -phenyl] - (1-imino-ethyl) -ammonium 5 (+) - (4R) 4-Benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol-2 ylamine (+) - (4R) -4- (4-ammobutyl) -4,5-dihydro-3-üûazol-2-ylamine (-) - (4S) -4- (3-nitrobenzyl) -4 5-Dihydro-1,3-thiazol-2-ylamine (-) - (4S, 5S) -4-benzyl-5-methyl-4) -5-dihydro-1,3-thiazol-2-ylquinoline ( -) - (4S) -4- (4-aminobutyl) -4,5-dihydro-3-ibiazol-2-yl lamine (4S, 5R) -4-bexizyi-5-methyl-4,5-dihydro-l, 3-tbiazol-2-ylamine (-) - (4R) -4-butyl-4,5-dihydro-1 3-Thiazol-2-ylamine (+) - (5S) -5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4S) -4-cyclohexykethyl-4,5 1H-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4-cyclohexylmethyl-4H-dihydro-1,3-thiazol-2-ylamine 4- (3-nitrophenyl) -4, 5-dihydro-l, 3-thiazol-2-yiamine (+) - (4R) -4- (4-pyridylméûiyl) -4,5-dihydro-l, 3-tbiazol-2-ylaniine (+) - (4RJ5R ) -5-methyl-4- (4-pyridylmethyl) -415-dih.ydro-l> 3-thiazol-2-ylamine (+) - (4R, 5R) -5-ethyl-4- (4-pyridylmethyl) -4,5-Dihydro-1,3-thiazol-2-ylaniine (+) - 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - 4- (5-thiazolylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine (+) - (4R) -4- (2-pyrazinylméthyl) -4,5-dihydro-1,3-thiazol-2 ylamine (4R) -4- (l-imidazolylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine (4S) -4- (l-imidazolylmethyl) -4,5-dihydro-3 Thiazol-2-ylam (+) - (4R) -4- (4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (3) aminopropyl) -4,5-dihydro-l , 3-thiazol-2-ylamine (+) - (4R) -4- (4-hydroxybenzyl) -4,5-dihydro-l} 3-thiazol-2-ylamme (+) - 4- (4-pyridylsulfanylméthyl) 4,5-Dihydro-1,3-thiazol-2-ylamineN (4R) -4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) 4- (1-Triazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine their tautomers as well as their pharmaceutically acceptable salts.

Particularly preferred are the compounds of formula (I) useful according to the invention for which R 1 is a hydrogen atom or an alkyl radical and R 2 is a radical-alk-NEfo, phenyl substituted with a radical -NH-C (= NH) CH3, -CH2-R3 or -CH2-S-R4R3 is a pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or phenyl radical substituted by a nitro or carboxy radical, R4 is a pyridyl radical.

Especially when R2 is a -CH2-R3 or -CH2-S-R4 chain, R3 is a 3- or 4-pyridyl radical, 2? or 3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl, 2-pyrazinyl, phenyl or phenyl substituted at the 3-position with a nitro oucaiboxy radical and R4 is a 4-pyridyl radical.

Among the compounds which are useful according to the invention and which are particularly preferred, mention may be made of the following compounds: 4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-nitrobenzyl) -4, 5-Dihydro-1,3-thiazol-2-ylamine 4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-thienylmethyl) -4,5-dihydro- 1,3-thiazol-2-ylamine 4- (2-thienylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro-thiazol-4-) yl) -phenyl] - (1-imino-ethyl) -amine 4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-carboxybenzyl) -4,5-dihydro-1, 3-thiazol-2-ylamine 4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol 2-ylamine-5-methyl-4- (4-pyridylethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro-1, 3-thiazol-2-ylamine 4- (4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol 2-ylamine 4- (2-pyrazinylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (5-thiazolylmethyl) 1) -4,5-Dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-triazolylmethyl) 4,5-dihydro-1,3-thiazol-2-ylamine, racemic, enantiomeric, diastereoisomeric, tautomeric and pharmaceutically acceptable salts thereof, and in particular the following compounds: (+) - (4R) -4- (3) pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5S) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine 1 ° (+) - (4R, 5R) -4-benzyl- 5-methyl-4,5-dihydro-l, 3-thiazol-2-ylamine (-) - (4R) -4- (3-thienylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine (4R) -4- (2-thienylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro-thiazol-4-yl) -phenyl] - (1-Imino-ethyl) -amine (+) - (4R) -4-Benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (3) -carboxybenzyl) -4,5-dihydro-l, 3-thiazol-2-ylamine (+) - (4R) -4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4S) -4- (3-nitroben2yl) -4,5-dibydro-l, 3-thiazol- 2-ylamine (-) - (4S, 5S) -4 ~ benzyl-5-methyl-4,5-dihydro-l, 3-thiazol-2-ylamine (-) - (4S) ~ 4- (4-aminobutyl ) -4,5-Dihydro-1,3-thiazol-2-ylamine (4S, 5R) -4-benyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (4-Pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -5-methyl-4- (4-pyridylmethyl) - 4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -5-ethyl-4- (4-pyridyhnéthyl) -4,5-dihydro-l, 3-thiazol-2 -ylamine (+) - 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - 4- (5-thiazolylmethyl) -4,5-dihydro-1, 3-thiazol-2-ylamine (+) - (4R) -4- (2-pyrazinylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine · (4R) -4- (1-imidazolylmethyl) -4,5-Dihydro-1,3-thiazol-2-ylamine (4S) -4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) 4- (4-Thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol 2-ylamine (+) - 4- (1-triazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine their tautomers as well as their pharmaceutically ac salts ceptable.

Compounds of formula (II) wherein R1 is methyl or hexyl and R2 is hydrogen or R1 and R2 are methyl are known as chemicals (J. Org Chem., 27, 1049 (1962); Org Chem., 37,4401 (1972), Beilstein RegistryNumbers 6114855, 6114856, 6117694, 6117695).

Moreover, certain compounds of formula (I) are known as radioprotecteurs.Ce are the racemic compounds for which R 1 is a methyl radical and R? is a hydrogen atom (Chem Abst., 1980, 92, 209060 and 209061),

R 1 is hydrogen and R 2 is methyl (Chem Abst, 1997, 87, 193910),

R 1 is hydrogen and R 2 is ethyl (Khim Geterotsikl, Soedin, 1987, 11, 1572),

R 1 is hydrogen and R 2 is n-propyl (Radiobiologiya, 1979, 19 (5), 671). The other compounds of formula (I) are new and as such form part of the invention as well as their racemic, enantiomers, diastereoisomers and tautomers and their pharmaceutically acceptable salts.

These are the compounds for which either R1 is a hydrogen atom or an alkyl radical and R1 is an alkyl radical, -alk-NE2, -CH2-R3, -CH2-S-R4 or phenyl substituted with a nitro radical or -NH-C (= NH) CH3, ie R1 is an alkyl radical and R2 is a hydrogen atom,

R 3 is a (3-6C) cycloalkyl, pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or phenyl radical substituted by a nitro, hydroxy or carboxy radical, R 4 represents a pyridyl radical, alk represents a radical; alkylene, their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts, with the exception of the compounds for which R 1 is hexyl or methyl and R 8 is hydrogen, or R 1 and R 2 are methyl and the racemics of the compounds for which R 1 is hydrogen and R2 is methyl, ethyl or n-propyl.

Particularly preferred compounds of formula (I) for which R 1 is a hydrogen atom or an alkyl radical and R 2 is a radical -alk-NHk, phenylsubstituted by a radical -NH-C (= NH) CH 3, -CH 2 -R 3 for which R3 is a pyridyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl, phenyl or phenyl radical substituted by a nitro or carboxy radical or -CH2-S-R4 for which R4 is a pyridyl radical, their racemates, enantiomers, diastereoisomers and mixtures thereof, theirautomers and their pharmaceutically acceptable salts.

In particular, R 3 is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl, 2-pyrazinyl, phenyl or phenyl radical substituted in the 3-position by a radical. nitro or carboxy and R4 is a 4-pyridyl radical.

Among the novel compounds of formula (I), mention may be made of the following compounds: 4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-nitrobenzyl) -4, 5-Dihydro-1,3-thiazol-2-ylamine 4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-thienylmethyl) -4,5-dihydro- 1,3-Thiazol-2-ylamine 4- (2-thienylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro-thiazole) 4-yl) -phenyl] - (1-imino-ethyl) -amine 4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-carboxybenzyl) -4,5-dihydro- 1,3-Thiazol-2-ylamine 4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylmethyl) -4,5-dihydro-1,3 Thiazol-2-ylamine-5-methyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-yiamine 5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro 1- (3-Thiazol-2-ylainin 4- (4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-imidazolylmethyl) -4H-dihydro-1,3-thiazole 2-ylamine 4- (2-pyrazinylmethyl) -4,5-dihydro-1H-3-triazol-2-ylquinine 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol 2-ylamine-4- (1-triazolylamethyl) -4,5-dihydro-1,3-thiazol-2-ylamine-4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine racers, enantiomers , diastereoisomers, tautomers and their pharmaceutically acceptable salts, and in particular the following compounds: (+) - (4R) -4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine ( +) - (4R) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5S) -4-benyl-5-methyl-4, 5-Dihydro-1,3-thiazol-2-ylaxine (+) - (4R, 5R) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4R) -4- (3-thiénylméthyî) -4,5-dihydro-l, 3-thiazol-2-ylamine (4R) -4- (2-thienylmethyl) -4,5-dihydro-3- thiazol-2-ylamine [3- (2-amino-4,5-dihydro-thiazol-4-yl) -phenyl] - (1-imino-ethyl) -ainin (+) - (4R) -4- benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine ( +) - (4R) -4- (4-Aminobutyl) -4,5-dihydro-1,3-tbiazol-2-ylamine (-) - (4S) -4- (3-nitrobenyl) -4,5- dihydro-1,3-thiazol-2-ylamine (-) - (4S, 5S) 4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4S) -4- (4-aminobutyl) -4,5-dihydro-1,3- thiazol-2-ylamine 12

U (4S, 5R) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (4-pyridylmethyl) -4, 5-Dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -5-methyl-4- (4-pyridylethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4RJ5R) -5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - 4- (5-thiazolylmethyl) -455 1-Dihydro-1,3-thiazol-2-ylamine (-) - 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- ( 2-pyrazinylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4R) -4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4S) 4- (1-Imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (4-thia2olylmethyl) -4,5-dihydro-1,3- thiazol-2-ylamine

Z (+) - 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - 4- (1-triazolylmethyl) -4,5-dihydro-1, 3-thiazol-2-ylamine their tautomers as well as their pharmaceutically acceptable salts. The invention also relates to pharmaceutical compositions containing as active principle a derivative of formula (T) for which either R 1 is a hydrogen atom or an alkyl radical and R 2 is an alkyl radical, -alk-NH 2, -CH 2 R3, -CH2-S-R4 or phenyl substituted with a nitro radical or -NH-C (= NH) CH3, or R1 is an alkyl radical and R2 is a hydrogen atom, R3. is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or phenyl radical substituted by a nitro, hydroxy or carboxy radical, R4 represents a pyridyl radical, alk represents an alkylene radical, and also its racemates , enantiomers, diastereoisomers and mixtures thereof, are automeric and pharmaceutically acceptable salts thereof. With the exception of the racemic compounds for which R 1 is methyl and R 2 is hydrogen or R 1 is hydrogen and R 2 is methyl, ethyl or n-propyl.

The compounds of formula (I) can be prepared by cyclizing a derivative of the formula: Ή (H)

in which R 1 and R 2 have the same meanings as in formula O).

This cyclization is generally carried out using an acid such as hydrochloric acid, in aqueous medium, at a temperature of 100 ° C. Preferably, 6N hydrochloric acid is used.

The derivatives of formula (Π) can be obtained according to the following reaction schemes:

Scheme 1 for compounds for which R 1 is hydrogen 14 012286

NHRa I

| Rg-CH-COOH

Rg-CH-CHgOH: d R Y nh2

## STR2 ##

NHCSNHC (CH3) 3.

R2-CH-CH2OH h

In these formulas R2 has the same meanings as in formula (I), Ra is a hydrogen atom or a protecting group for the amine function such as those described by T.W. GREENE, Protective groups in Organic Synthesis, J. Wiley-Intèrscience Publication (1991) and Rb is a (1-4C) alkyl radical or alkoxycarbonyl, preferably, methyl, ethyl or isobutyloxycarbonyl. Preferably, the protecting group of the amine function is an acetyl or tert-butoxycarbonyl radical.

The reaction is generally carried out in the presence of sodium (1-4C) alkoxide (preferably sodium ethoxide) in the corresponding alcohol at a temperature of between 10 ° C. and the boiling point. of the reaction medium. 15 01 22 8 €

Reaction b is generally carried out in an inert solvent such as dimethylformamide in the presence of lithium iodide, at a temperature of between 100 ° C. and the boiling temperature of the reaction medium, or else in an alcoholaliphatic alcohol ( 1-4C), in the presence of sodium hydroxide, at a temperature of 10 to 30 ° C followed by neutralization with 6N HCl and then heating in a solvent such as ledioxanne at a temperature of 100 ° C .

The reaction is carried out preferably with hydrochloric acid at a temperature of 100 ° C.

The reaction b "for the derivatives for which Rb is an alkyl radical is generally carried out by the action of an aliphatic alcohol (1-4C) (methanol, preferably ethanol), in the presence of a mineral acid such as the acid. sulfuric acid, at a temperature between 50 ° C and the boiling temperature of the reaction medium.For the derivatives for which Rb is an isobutyloxycarbonyl radical, this reaction is generally effected by the action of isobutyl choroformate in the presence of a base such as that triethylamine, in an inert solvent such as tetrahydrofuran, at a temperature between -20 ° C and 0 ° C.

The reduction reactions, c, g and i, are preferably carried out by means of a hydride such as sodium borohydride or lithium aluminum hydride, in a (1-4 C) aliphatic alcohol or tetrahydrofuran, at a temperature of at a temperature of between 10 ° C. and 30 ° C., or by means of a borane derivative such as the BH3-THE complex, in a solvent such as tetrahydrofuran, at a temperature of between 0 ° C. and 30 ° C. ° C.

The deprotection reaction d for the compounds for which Ra is a protective group of the amine function is carried out by any deprotection method known to those skilled in the art and in particular those described by T.W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out with aqueous hydrochloric acid at a temperature of 100 ° C. When the protective group is a tert-butoxycarbonyl radical, this reaction is carried out by means of hydrochloric acid in dioxane, at a temperature in the region of 20 ° C.

Reactions e and h are carried out by the action of tert-butyl isothiocyanate, in an inert solvent such as an aliphatic alcohol (1-4C) (methanol, ethanol preferably), optionally in the presence of a tertiary amine such as triethylamine, at a temperature of between 20 ° C. and the boiling temperature of the reaction medium.

The reaction is carried out by the action of an aliphatic alcohol (1-4C) (methanol or ethanol preferably), in the presence of a mineral acid such as hydrochloric acid, at a temperature between 20 ° C. and the temperature of 20 ° C. boiling of the reaction medium 10 or by the action of thionyl chloride, in an aliphatic alcohol (1-4C) (preferably methanol or ethanol), at a temperature between -25 ° C and 30 ° C.

Scheme 2 for Compounds for Which R 1 is Alkyl 17 012286 NHRa NHRa + h, c-o-nh-ch3

R 8 -CH-COORb 3 NHRa R 2 -CH-CO-N (CH 3) OCH 3 R 2 -CH-CORl NH-R-CH-CHOH-R,

NHR

Embedded image in these formulas R 1 and R 2 have the same meanings as in formula (I), Ra is a hydrogen atom or a protecting group of the formula (I), and R 2 -CH-CHOH-R, NHCSNHC (CH 3) 3 R 2 -CH-CHOH-R 1 amine function such as those written by TW GREENE, Protective group in Organic Synthesis, J. Wiley-Interscience Publication (1991) and, preferably, an acetyl or tert-butoxycarbonyl radical and Rb is an alkyl or alkoxycarbonyl radical and, preferably, methyl, ethyl or isobutyloxycarbonyl.

The reaction is preferably carried out in an inert solvent such as a chlorinated solvent (chloroform or dichloromethane, for example), optionally in the presence of a base such as N-methylmorpholine or triethylamine, at a temperature of 50.degree. between -15 ° C and 30 ° C.

A 18 012286

Reaction b is carried out by the action of an alkylmagnesium halide such as an alkyl magnesium bromide, in an ether such as tetrahydrofuran or ether, at a temperature between 0 ° C. and 30 ° C. .

The reduction reaction c is preferably carried out by means of a hydride such as sodium borohydride or lithium aluminum hydride, in a (1-4 C) aliphatic alcohol or tetrahydrofuran, at a temperature of between 10 ° C and 30 ° C, or using a borane derivative such as the BH3-THF complex, in addition to a solvent such as tetrahydrofuran, at a temperature between 0 ° C and 30 ° C. The deprotection reaction is carried out by any deprotection method known to those skilled in the art of an amine function and especially those described by TWGREENE, Protective group in Organic Synthesis, J. Wiley-Interscience Publication ( 1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out by means of aqueous hydrochloric acid at a temperature of 100 ° C. When the protecting group is a tert-butoxycarbonyl radical this reaction is carried out by means of hydrochloric acid in dioxane at a temperature of about 20 ° C.

The reaction is carried out by the action of tert-butyl isothiocyanate, in a solvent such as an aliphatic alcohol (1-4C) (methanol, ethanol preferably), in the presence of a tertiary amine such as triethylamine, at a temperature between 20 ° C and the boiling temperature of the reaction medium.

The compounds of formula (I) for which R2 is a phenyl radical substituted with unradical -NH-C (= NH) CH3 may also be prepared from the corresponding amine derivatives themselves obtained by reduction of the nitro derivatives of formula (I) according to the following scheme: 6 19 012286

The reduction reaction is carried out by any reduction method known to those skilled in the art to pass from a nitro to an amino without affecting the rest of the molecule. Preferably, zinc is used in acetic acid at a temperature in the region of 20 ° C.

Reaction b is carried out by reaction of benzylethanimidothioate hydrochloride, with the aid of an inert solvent such as an aliphatic alcohol (1-4C) and preferably methanol or ethanol, at a temperature between 0 ° C and 45 ° C.

The intermediates of formula (HT) are new and form part of the invention. Compounds of formula (I) wherein R2 is -CH2-R3 in which R3 is 1-imidazolyl or 1- (1,2,4-triazolyl) can also be prepared by the action of imidazole or 1, 2,4-triazole on a derivative of formula:

(IV) wherein R 1 has the same meanings as in formula (I), X is a halogen atom and, in particular, an iodine atom, or a tosyl radical, Ra and Rb are l 012286 atoms of hydrogen or protecting groups of the amine function such as those described by TW GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butyloxycarbonyl, followed optionally by deprotection. This reaction is generally carried out in the presence of a base such as an alkali metal hydride, preferably sodium hydride, in a solvent such as dimethylsulfoxide, at a temperature of between 20 ° C. and the temperature. boiling of the reaction medium.

The deprotection reaction for compounds for which Ra or Rb is a group protecting the amine function is carried out by any deprotection method known to those skilled in the art and in particular those described by T.W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out with aqueous hydrochloric acid at a temperature of 100 ° C. When the protective group is a tert-butyloxycarbonyl radical, this reaction is carried out by means of hydrochloric acid in dioxane, at a temperature in the region of 20 ° C.

The compounds of formula (IV) can themselves be obtained according to the following schema-reaction:

c

(IVa)

In these formulas, R 1 has the same meaning as in formula (1), Ts is a tosylate radical, Ra and Rb are a hydrogen atom or a protecting group for the amine function such as those described by T.W. GREENE, Protective groups in Organic

I 22 012286

Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butyloxycarbonyl.

The reaction is generally carried out by the action of tert-butyl isothiocyanate, in the presence of an inert solvent such as an aliphatic alcohol (1-4C) (methanol, ethanol preferably), optionally in the presence of a tertiary amine such as than triethylamine, at a temperature between 20 ° C and the boiling point of the reaction medium.

The cyclization reaction b is generally carried out by means of an acid such as hydrochloric acid, in an aqueous medium, at a temperature in the region of 100 ° C. Preferably, 6N hydrochloric acid is used.

The reactions c and g when Ra or Rb is a tert-butoxycarbonyl group are carried out by any method of protection known to those skilled in the art and in particular those described by T.W. GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). This reaction is preferably carried out by means of bis-tert-butyl dicarbonate, in the presence of a base such as triethylamine and optionally in the presence of 4- (dimethylamino) pyridine, in a solvent such as dichloromethane. and at a temperature of 20 ° C, or in the presence of a base such as potassium carbonate, in a solvent such as water and at a temperature of 20 ° C. The reaction is generally carried out by the action of p-toluene sulphonyl chloride, the presence of a tertiary amine such as triethylamine, in a solvent inertetel dichloromethane, at a temperature between 20 ° C and the temperature of boiling of the reaction medium.

The reaction is generally carried out by the action of sodium iodide, in an inert solvent such as acetone, at a temperature between 20 ° C and the boiling temperature of the reaction medium.

The reaction is generally carried out by the action of an allyl halide, for example allyl chloride, in an aliphatic alcohol (1-4C), preferably ethanol, at a temperature of from 0.degree. between 20 ° C and the boiling point of the reaction medium.

The reaction is generally carried out by the action of iodine, in the presence of a base such as sodium bicarbonate, in a solvent such as dichloromethane, at a temperature of between 20 ° C. and the temperature of 20.degree. boiling of the reaction medium.

The compounds of formula (Γ) for which R 2 is a radical -CH 2 -S-R 4 may beprepared by the action of a compound of formula (IVa) or (IVb) corresponding to a derivative of formula HS-R 4 in which R 4 has the same Significantly in the formula (R), Ra and Rb are hydrogen atoms or protecting groups of the amine function such as those described by TW GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or acetyl and more particularly tert-butyloxycaibonyl optionally followed by deprotection of the amine function. This reaction is generally carried out in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile or dimethylformamide (preferably acetonitrile), at a temperature of between 20 ° C. and the temperature of 50.degree. boiling of the reaction medium.

The deprotection reaction for the compounds for which Ra or Rb is a group protecting the amine function is carried out by any deprotection method known to those skilled in the art and in particular those described by T.W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably, when the protecting group is an acetyl radical, this reaction is carried out with aqueous hydrochloric acid at a temperature of 100 ° C. When the protective group is a tert-butoxycarbonyl radical this reaction is carried out by means of hydrochloric acid in the dioxane, at a temperature of 20 ° C. The compounds of formula (Γ) are isolated and can be purified by the usual known methods, for example by crystallization, chromatography or extraction. 1 »24 012286

The enantiomers of the compounds of formula (I) can be obtained by doubling the racemates, for example by chromatography on chiral columns according to PIRCKLE W.H. et al., Asymmetric synthesis, vol. 1, Academic Press (1983) or by salt formation or synthesis from chiral precursors. The diastereoisomers can be prepared according to known conventional methods (crystallization, chromatography or from chiral precursors).

The compounds of formula (I) may optionally be converted into addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a solvent chlorine. These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, mention may be made of the following salts: benzenesulphonate, hydrobromide, hydrochloride, citrate, ethanesulphonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulphonate, methylene-bis-b-oxynaphthoate, nitrate, oxalate, pamoate, phosphate salicylate, succinate, sulfate, tartrate, theophyllinacetate and p-toluenesulfonate.

The compounds of formula (I) are inhibitors of inducible NO-synthase or NO-• synthase type 2 (NOS-2) and are thus useful for the prevention and treatment of disorders related to excessive production of NO such as sclerosis in plaques, focal or global cerebral ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic sclerosalateral, migraine, depression, schizophrenia, anxiety • epilepsy, diabetes, atherosclerosis, myocarditis, arthritis, osteoarthritis, asthma, irritable bowel syndrome, Crohn's disease, peritonitis, gastroesophageal reflux disease, uveitis, Guillain-Barré syndrome, glomerulo-nephritis, lupus erythematosus, psoriasis, the growth of certain forms of tumors such as, for example, epitheliomas, adenocarcinomas or sarcomas, and infections with intestinal bacteria. racellular or extracellular, gram-plus or gram-minus. 012286

Their activities as inhibitors of NOS-2 and NOS-3 were determined by the size of the conversion of [3H] -L-arginine to [3H] -L-citrullme by, respectively, a NOS-2 enzymatic fraction extracted. from lungs of rats or mice pre-treated with lipopolysaccharides (10 mg / kg ip 6 hours before tissue collection) and a commercial preparation of recombinant NOS-3 beef.The compounds were incubated for 20 to 30 minutes at 37 ° C C in the presence of 5 μΜ (for NOS-2 activity) or 10 μΜ (for NOS-3 activity) of [^ TJ-L-arginine, 1 mM of NADPH, 15 μΜ of tetrabiopterin, ΙμΜ of F AD, 0.1 mM of DTT in HEPPE buffer (50mM, pH 6.7) containing 10g / ml calmodulin and 25mM CaCl2 when NOS-3 activity was measured. Incubation was stopped by addition of cold HEPES buffer (100 mM, pH 5.5) containing 10 mM EGTA and 500 mg cationic cation exchange unesin (AG50W-X8, counter-ion: Na4) to separate [3H] -L-arginine of [3H] -L-citrulline. After 5 min of decantation, the radioactivity in the liquid phase was measured in a scintillation counter in the presence of a suitable scintillation liquid. The recovery yield of the L-α-carbullin formed could be estimated using L- [ureidp-, 4C] -citrullin as an external standard. NOS-2 or NOS-3 activity was expressed as picomol (s) of [hT] -L-citrulline per minute and per milligram of protein contained in the reaction medium.

In this test on the NOS-2 enzyme, the IC50 of the compounds of formula (I) is less than or equal to 10 μl.

The selectivity is measured by the IC50 NOS-3 / IC50 NOS-2 ratio. This selectivity is greater than 20.

The compounds of formula (I) have low toxicity. Their LD50 is greater than 40 mg / kg subcutaneously in mice.

The following examples illustrate the invention. 26 012286

Example 1

(+) - (4R) -4- (3-Pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride

A suspension of 3.35 g of N- (ieri-butyl) -N '- [(1R) -2-hydroxy-1- (3-pyridylmethyl) ethyl] thiourea in 32 cm3 of 6N hydrochloric acid is heated to a temperature of 100 ° G for 5 hours then the heating is stopped. The solution is then evaporated under reduced pressure (2 KPa) at a temperature in the region of 50 ° C. 4.42 g of a yellow oil is obtained which becomes pasty. This paste is taken up in acetone and evaporated again under reduced pressure (2 kPa) at a temperature of 40 ° C. The residue is taken up in diethyl ether. Light beige colored crystals are obtained, which are filtered on sintered glass, then washed with diethyl ether and dried in the oven under reduced pressure (0.1 kPa) at a temperature of about 50.degree. 3.28 g of (+) - (4R) -4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride are obtained in the form of a sandy solid of light beige color, melting at 124 ° C [NMR spectrum] (300 MHz, (GD3) 2SOd6, δ in ppm): 3.20 (mt: 2H); 3.40 (dd, J = 11 and 5 Hz: 1H); 3.70 (dd, J = 11 and 8Hz: 1H); 4.67 (mt: 1H); 7.97 (dd, J = 8 and 5.5 Hz: 1H); 8.46 (broad d, J = 8 Hz: 1H), 8.83 <broad, J = 5.5 Hz: 1H); 8.90 (d, J = 2 Hz: 1H); 9.28 (mf: 1H); 9.75 (mf: 1H); 10.30 (mf: 1H); (an20 = + 18.3 +/- 0.7 in 0.5% methanol) N- (ieri-butyl) -N '- [(1R) -2-hydroxy-1- (3-pyridylmethyl) ethyl] thiourea: To the suspension under an inert atmosphere of 16.51 g of (2R) -2-amino-3- (3-pyridyl) -1-propanol dihydrochloride in 200 cm 3 of ethanol, is added dropwise 22, 7 cm3 of triethylamine, then 14 cm3 of isofiocyanate of zerf-butyl The mixture is then heated to a temperature of 60 ° C for 1 hour 30 min .. Aftercooling at a temperature of 20 ° C, the insoluble material is filtered off. After the reaction, the filtrate is evaporated under reduced pressure (2 kPa) at a temperature of 40 ° C. A yellow paste is obtained which is taken up in 200 cm 3 of ethyl acetate and 100 cm 3 of water. washed with 2 times 200 cm3 of ethyl acetate, the organic phases are combined, washed with 3 times 50 cm3 of

Saturated solution of sodium chloride, and dried over magnesium sulfate. After filtration and evaporation under reduced pressure (2 kPa) at a temperature in the region of 40 ° C., a yellow oil is obtained which is taken up in dichloromethane and evaporated to give 3.25 g of N- (ieri-butyl) -N'- [(1 R) -2-hydroxy-1- (3-pyridylmethyl) ethyl] thiourea as a pale yellow meringue [NMR Spectrum] (400 MHz, (CD3) 2 SO d6, δ in ppm): 1.41 (s: 9H); 2.84 (mt: 2H); 3.37 (mt: 2H); 4.43 (mf: 1H); 4.96 (t, J = 5 Hz: 1H); 7.24 (d, J = 8 Hz: 1H); 7.27 (slarge: 1H); 7.33 (dd, J = 8 and 5 Hz: 1H); 7.67 (dt, J = 8 and 2 Hz: 1H); 8.42 (dd, J - 5 and 2 Hz: 1H); 8.46 (d, J = 2 Hz: 1H)]. -

(2R) -2-amino-3- (3-pyridyl) -1-propanol dihydrochloride: A suspension of 13.55 g of N - [(1R) -2-hydroxy-1- (3-pyridylmethyl) ethyl] acetamide in 110 cm3 of 6N aqueous hydrochloric acid is heated at a temperature in the region of 100 ° C. for 3 hours. The water is evaporated under reduced pressure (3 fcPa) at a temperature in the region of 50 ° C. 16.51 g of (2R) -2-amino-3- (3-pyridyl) -1-propanol dihydrochloride are obtained in the form of an off-white solid (NMR Spectrum). H (400 MHz, (CD3) 2SO d6, δ in ppm): 3.13 (d, J = 7.5 Hz: 2H); 3.50 (mt: 2H); 3.62 (mt: 1H); 7.94 (dd, J = 8 and 5.5 Hz: 1H); 8.27 (mf: 3H); 8.43 (broad d, J = 8 Hz: 1H); 8.79 (broad, J = 5.5 Hz: 1H); 8.86 (bs: 1H) N - [(1R) -2-hydroxy-1- (3-pyridylmethyl) ethyl] acetamide: An inert submosphere solution of 20.77 g (2R) -2- (acetylamino) Ethyl 3- (3-pyridyl) propanoate in 208 cm3 of anhydrous ethanol is cooled to a temperature in the region of 10 ° C., 8.31 g of sodium borohydride are then added in portions, and the reaction mixture is stirred for 16 hours at room temperature. At room temperature, the ethanol is evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C., to give 43.56 g of a pale yellow paste which is taken up and stirred in 50 cm 3 of water. The solution, which has a pH of about 12, is cooled to a temperature in the region of 0 ° C. and then neutralized by addition of dropwise concentrated hydrochloric acid.The mixture is stirred for 1 hour at that temperature, and the white precipitate formed is filtered off on sintered glass and then dried. in the oven under vacuum (0.1 kPa) at a temperature in the region of 55 ° C. 11.15 g of N - [(1R) -2 - 28 01 228 are obtained. - hydroxy-1- (3-pyridylmethyl) ethyl] acetamide as a white solid melting at a temperature above 260 ° C. The filtrate is extracted with 3 times 100 cm3 of ethyl acetate and then the organic phases are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2 fcPa) at a temperature in the region of 40 ° C. 2.4 g of N - [(1R) -2-hydroxy-1- (3-pyridylmethyl) ethyl] acetamide partially complexed with boron in the form of a white paste are obtained [NMR spectrum (300 MHz, (CD3) 2SO d6 δ in ppm): 1.75 (s: 3H); 2.61 (dd, J = 14 and 9 Hz: 1H); 2.88 (dd, J = 14 and 5.5 Hz: 1H); from 3.20 to 3.45 (mt: 2H); 3.91 (mt: 1H); 4.82 (tlarge, J = 5 Hz: 1H); 7.30 (dd, J = 7.5 and 5 Hz: 1H); 7.62 (dt, J = 7.5 and 2 Hz: 1H); 7.72 (d, J = 9 Hz: 1H); from 8.35 to 8.45 (mt: 2H)]. Ethyl r (2R) -2- (acetylamino) -3- (3-pyridyl) propanoate: A suspension of 54.7 g of ethyl 2- (acetylamino) -3- (3-pyridyl) propanoate in 420 cm3 of water, to which is added 18.5 g of potassium chloride, is solubilized by addition of 100 cm3 of acetonitrile. A neutral orange solution is obtained, then 0.168 g of α-chymotrypsin is added and the pH decreases. A 2N aqueous solution of potassium hydroxide is added dropwise with stirring to keep at a constant pH of 1. After 1 hour 30 minutes, the pH varies little, the mixture is stirred for 48 hours at room temperature. The pH of the solution is then approximately 5.6 and then, by addition of the aqueous solution of 2N potassium hydroxide, it is adjusted to approximately 7. 0.084 g of α-chymotrypsin is introduced, and the pH is adjusted to 7, 2 by a further addition of 2N aqueous potassium hydroxide solution and stirring for 1 hour 30 min. The pH of the reaction medium did not vary. 400 cm3 of ethyl acetate are added, the mixture is stirred for 30 minutes and then filtered through celite. The filtrate is decanted and the aqueous phase is extracted with 3 times 400 cm 3 of ethyl acetate. The organic phases are combined, washed with 400 cm of saturated sodium chloride solution and dried over magnesium sulfate. After filtration and concentration under reduced pressure (2 kPa) at a temperature in the region of 40 ° C., 20.77 g of ethyl (2R) -2- (acetylamino) -3- (3-pyridyl) propanoate are obtained in the form of a beige solid at 80 ° C. [NMR spectrum] (400 MHz, (CD3) 2SO d6, δ in ppm): 1.13 (t, ft 29 .01 2286 J = 7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd, J = 14 and 9.5 Hz: 1H); 3.05 (dd, J = 14 and 5.5 Hz: 1H); 4.07 (q, J = 7 Hz: 2H); 4.48 (mt: 1H); 7.33 (dd, J = 8 and 5 Hz: 1H); 7.66 (dt, J = 8 and 2 Hz: 1H); 8.36 (d, J = 8 Hz: 1H); 8.44 (mt: 2H)]. 2- (Ethyl acetylamino) -3- (3-pyridyl) propanoate: To a solution of 51.4 g of diethyl 2- (acetylamino) -2- (3-pyridylmethyl) malonate in 857 cm3 of ethanol is added dropwise 44.45 cm3 of 6N aqueous sodium hydroxide. The mixture is stirred for 1 hour 30 minutes at a temperature in the region of 20 ° C. and then cooled to a temperature in the region of 0 ° C. 22.2 cm3 of 12N hydrochloric acid are added dropwise; a precipitate is formed. It returns to room temperature and then after 2 hours of stirring / the pH of the reaction medium is 5-6. It is concentrated under reduced pressure (4 μPa) at a temperature in the region of 50 ° C. to give a dark beige sticky solid which is dried for 16 hours in the oven under vacuum (0.1 μCa) at a temperature in the region of 50 ° C. This residue is taken up with 1000 cm3 of dioxane and then heated to a temperature of 100 ° C for 1 hour. The dioxane is evaporated under reduced pressure (2 fcPa) at a temperature of 40 ° C and the residue is dissolved in 250 cm 3 of water.

It is neutralized by addition of 4 cm3 of 10N aqueous sodium hydroxide and then 750 cm3 of ethyl acetate are added. After decantation, the organic phase is extracted and the phaseaqueuse is washed with 2 times 300 cm3 of ethyl acetate. The organic phases sontréunies, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2 kPa) at a temperature of 40 ° C. The solid residue obtained is taken up in 70 cm3 of ethyl acetate and 20 cm3 of heptane and then filtered on sintered glass. 27.76 g of ethyl 2- (acetylamino) -3- (3-pyridyl) propanoate are obtained in the form of a beige solid which melts at 118 ° C. [NMR Spectrum]. (400 MHz, (C max, SO d6, δ enppm): 1.13 (t, J = 7 Hz: 3H), 1.81 (s: 3H), 2.92 (dd, J = 14 and 9 Hz: 1H), 3.04 (dd, J = 14 and 5.5 Hz: 1H), 4.07 (q, J = 7 Hz: 2H), 4.48 (mt: 1H), 7.33 (dd, J = 8 and 5 Hz: 1H), 7.66 (dt, J = 8 and 2 Hz: 1H), 8.38 (d, J = 8 Hz: 1H), 8.45 (mt: 2H)]. Re-extralating the aqueous phase with 2 times 500 cm3 of ethyl acetate and drying and concentration under reduced pressure of the combined organic phases, 4 g of ethyl 2- (acetylamino) -3- (3-pyridyl) propanoate are recovered. in the form of a yellow-beige solid solution melting at 121 ° C.

In the same way, starting from 50.2 g of diethyl 2- (acetylamino) -2- (3-pyridylmethyl) malonate, 26.94 g of ethyl 2- (acetylamino) -3- (3-pyridyl) are obtained. ) propanoate. 2- (Acetylamino) -2- (3-pyridylmethyl) malonate diethyl: To 600 cm3 of ethanol, 17.2 g of sodium hydroxide, previously twice with pentane, are added in small portions, with stirring under an inert atmosphere. After total consumption of sodium, 73.5 g of diethyl acetamidomalonate are added rapidly and the mixture is allowed to stir for 30 minutes. at a temperature of 40 ° C. A suspension of 56 g of di-3-picolyl chloride hydrochloride in 300 cm3 of ethanol is then added quickly and the resulting pinkish suspension is stirred for 44 hours at a temperature of 20 ° C. 28.1 g of potassium iodide are added, and the stirring is continued at room temperature for 4 hours and finally heated at a temperature of 50 ° C. for 44 hours. The mixture is cooled to a temperature in the region of 0 ° C. and then filtered on a sintered glass to remove the salts which are washed with ethanol. The filtrate is concentrated under reduced pressure (2 kPa) at a temperature close to 40 ° C. A brown paste is obtained, which is dissolved in 100 cm 3 of water and treated with 7 cm 3 of a 3N aqueous hydrochloric acid solution until a pH of about 6 is reached. The mixture is placed in the refrigerator for 48 hours. The crystalline precipitate obtained is filtered on sintered glass, washed with 50 cm3 of ice water, drained and then dried in a desiccator under reduced pressure (5 kPa) for 16 hours. After drying in the oven under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. for 4 hours, 50.2 g of diethyl 2- (acetylamino) -2- (3-pyridylmethyl) malonate are obtained in the form of a beige-solid solid at 96 ° C. [Spectrum NMR 1h (400 MHz, (CD3) 2SO d6, δ in ppm): 1.19 (t, J = 7 Hz: 6H); 1.97 (s: 3H); 3.47 (s: 2H); 4.17 (q, J = 7 Hz: 4H); 7.33 (dd, J = 8 and 5Hz: 1H); 7.41 (dt, J = 8 and 2 Hz: 1H); 8.21 (d, J = 2 Hz: 1H); 8.24 (s: 1H); 8.47 (dd, J = 5 and 2 Hz: 1H)]. 012286 31

Example 2 (+) - (4R) -4- (3-Nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride

1 g of N- (tert-butyl) -2V - [(1R) -2-hydroxy-1- (3-nitrobenzyl) ethyl] thiourea are heated for 5 hours at a temperature in the region of 100 ° C. cm3 of acid

6N hydrochloric acid. The reaction medium is then cooled to a temperature in the region of 0 ° C .; a white precipitate is formed which is filtered on sintered glass and then washed with 20 cm3 of diethyl ether. The cake is then dried in a desiccator under vacuum. 0.68 g of (+) - (4R) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine, hydrochloride in the form of beige crystals melting at 232.degree. ° C [NMR spectrum. (300 MHz, (CD ^ SO d6, δ in ppm): 3.15 (AB limit: 2H), 3.25 to 3.45 (mt: 1H), 3.63 (dd, J = 13 and 8) Hz: 1H), 4.62 (mt: 1H), 7.68 (t, J = 8Hz: 1H), 7.81 (broad d, J = 8 Hz: 1H), 8.18 (broad d, J = 8 Hz: 1H), 8.24 (s wide: 1H), 9.00 to 10.40 (mf: 3H), (aD20 = +18.8 +/- 0.6 in the methanol at 0, 5%)] 77- (ieri-Butyl) -7 '- [(1 R) -2-hydroxy-1- (3-nitrobenzyl) ethyl] triolourea: A suspension of 0.92 g of (2 R) -2 -amino-3- (3-nitrophenyl) -1-propanol, hydrochloride and 0.6 cm3 of 4-butylisothiocyanate in 10 cm3 of ethanol is cooled to a temperature of 0 ° C and then is added 0.56 cm3 of triethylamine The mixture is stirred for 18 hours at room temperature and is then heated at a temperature in the region of 60 ° C. for 2 hours, the suspension is then dissolved, 0.6 cm.sup.3 of tert-butyl isothiocyanate is added and heating is continued for 3 hours then onconcentre the reaction medium under reduced pressure (2kPa) at a temperaturevo isine of 50 ° C. The yellow oil obtained is dissolved in 50 cm 3 of ethyl acetate and the organic solution is then washed with 2 times 50 cm 3 of a sodium chloride solution, dried over sodium sulphate, filtered and concentrated. under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 1.2 g of 77- (Fe7'r-butyl) -7V - [(1R) -2-hydroxy-

1- (3-nitrobenzyl) ethyl] thiourea as a yellow oil [NMR spectrum (300 MHz, (CD3) 2SO d6 with addition of a few drops of CDjCOOD d4, δ in ppm): 1.39 (s: 9H); 2.98 (AB limit: 2H); 3.38 (AB limit: 2H); 4.48 (mt: 1H); 7.60 (t, J

I 32 .012286 = 8 Hz: 1H); 7.74 (broad d, J = 8 Hz: 1H); 8.09 (broad d, J = 8 Hz: 1H); 8.16 (slarge: 1H)]. (2R) -2-Amino-3- (3-nitrophenyl) -1-propanol hydrochloride: A suspension of 0.98 gN - [(1R) -2-hydroxy-1- (3-nitrobenzyl) ethyl] acetamide in 10 cm3 of 6N hydrochloric acid is heated at a temperature of 100 ° C for 10 hours (solubilization). The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature of 40 ° C. The residue is taken up in 20 cm3 of diethyl ether and evaporated again under the same conditions to give beige crystals which are washed with 3 times 20 cm3 of diethyl ether and then filtered on sintered glass and put under ventilated hood. 0.92 g of (2R) -2-amino-3- (3-nitrophenyl) -1-propanol, hydrochloride, are obtained in the form of beige crystals melting at 192 ° C. [NMR Spectrum]. TH (250 MHz, (CD3) 2SO d6, δ in ppm): 3.06 (AB limit: 2H), from 3.25 to 3.65 (mt: 3H); 5.45 (ζ J = 4.5 Hz: 1H); 7.65 (t, J = 7 Hz: 1H); 7.79 (broad, J = 7 Hz: 1H); from 8.05 to 8.40 (mt: 5H)]. N - [(1R) -2-Hydroxy-1- (3-nitrobenzyl) ethyl] acetamide: A slight suspension, inert atmosphere, of 1.4 g of (2R) -2- (acetylamino) -3- (3- nitrophenyl) ethyl propanoate in 13 cm3 of ethanol is cooled to a temperature of 20 ° C and then added to 0.29 g of sodium borohydride. The yellow solution obtained is stirred at ambient temperature for 18 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 50 ° C., then 10 cm 3 of water are added and the mixture is extracted twice with 50 cm 3 of ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 1 g of N - [(1R) -2-hydroxy-1- (3-nitrobenzyl) ethyl] acetamide are obtained in the form of pale yellow-colored crystals melting at 135 ° C. [NMR Spectrum]. H (250 MHz, (CD3) 2SO d6, δ in ppm): 1.75 (s: 3H); 2.74 (dd, J = 14 and 9 Hz: 1H); 3.02 (dd, J = 14 and 5 Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.96 (mt: 1H); 4.90 (brs: 1H); 7.59 (t, J = 8 Hz: 1H); 7.70 (broad, J = 8 Hz: 1H); 7.82 (d, J = 8.5 Hz: 1H); from 8.05 to 8.15 (mt: 2H)]. Ethyl 0-2: 0- (2R) -2- (acetylamino) -3- (3-nitrophenyl) propanoate: A mixture of 2.8 g of ethyl 2- (acetylamino) -3- (3-nitrophenyl) propanoate in 17 cm3 of acetonitrile, 3.95 g of ammonium hydrogencarbonate and 35 cm 3 of water are added to a pH of about 8. 0.017 g of α-chymotrypsin type Π are then introduced and the mixture is stirred at room temperature. for 1 hour 15 min. By regularly measuring the pH. After this reaction time, the pH is less than 8, 0.017 g of α-chymotrypsin type Π is added again and stirring of the reaction medium is continued for 2 hours 45 min. aqueous phase with 3 times 50 cm3 of ethyl acetate; the combined organic phases are then dried over sodium sulphate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 1.4 g of ethyl (2R) -2- (acetylamino) -3- (3-nitrophenyl) propanoate are obtained in the form of white crystals, melting at 110 ° C. Ethyl 2- (acetylamino) -3- (3-nitrophenyl) propanoate: To 12 g of ethyl 2-amino-3- (3-nitrophenyl) propanoate at a temperature in the region of 0 ° C. is added dropwise. dropwise 9.52 cm3 of acetic anhydride. Stir at 0 ° C for 1 hour and mix. 10 cm3 of acetic anhydride are then added and stirring is continued at 0 ° C. for a further 1 hour. The precipitate is filtered on sintered glass, washed with 3 times 25 cm3 of water, dried under ventilated hood and then in the oven under vacuum (10 Pa) at a temperature of 50 ° C. 12 g of ethyl 2- (acetylamino) -3- (3-nitrophenyl) propanoate are obtained in the form of white crystals melting at 91 ° C. [NMR Spectrum]. 1 H (250 MHz, (CD3) δ SO4, δ in ppm): 1.14 (t, J = 7 Hz: 3H), 1.80 (s: 3H); 3.04 (dd, J = 14 and 9 Hz: 1H); 3.18 (ζ J = 14 and 4 Hz: 1H); 4.08 (q, J = 7 Hz: 2H); 4.52 (mt: 1H); 7.61 (broad t, J = 8 Hz: 1H); 7.72 (broad, J = 8 Hz: 1H), 8.12 (mt: 2H); 8.42 (d, J = 8.5 Hz: 1H)]. Ethyl 2-Ammo-3- (3-nitrophenyl) propanoate: In a mixture of 23.4 g of 3-nitrophenylalanine hydrochloride in 300 cm3 of ethanol cooled to a temperature of about 0.degree. gaseous hydrochloric acid until saturation. Lasuspension obtained is heated to a temperature of 78 ° C for 18 hours: there is hot dissolution of this suspension. We stop the heating, we oil

In the solution, gaseous hydrochloric acid is added for 15 minutes. and heated again to a temperature of 78 ° C for 70 hours. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 50 ° C. and the residue is then basified to a pH of approximately 10 with a sodium carbonate solution. This aqueous phase is extracted with 3 times 100 ml of dichloromethane and the combined organic phases are dried over sodium sulphate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. to give 12.2 g of 2-amino Ethyl 3- (3-nitrophenyl) propanoate as an orange oil [NMR spectrum] H (250 MHz, (CD 2 SO 4 d 6, δ in ppm): 1.14 (t, J = 7 Hz: 3H), 1.88 (mf: 2H), 2.92 (dd, J = 13 and 7 Hz (λH), 3.02 (dd, J = 13 and 6 Hz: 1H), 3.62 (dd, J = 7 and 6 Hz: 1H), 4.05 (q, J = 7 Hz: 2H), 7.59 (t split, J = 8.5 and 1.5 Hz: 1H), 7.71 (d broad, J = 8 Hz: 1H), from 8.05 to 8.20 (mt: 2H] 3-Nitrophenylalanine hydrochloride: A suspension of 34 g of diethyl 2- (acetylamino) -2- (3-nitrobenzyl) malonate in 510 cm3 of concentrated hydrochloric acid is heated to a temperature of about 1.00 ° C. for 18 hours. hours: a large gaseous evolution occurs and the suspension is solubilized hot.The reaction mixture is then cooled to a temperature of 0 ° C and then stirred for 1 hour at 0 ° C and finally filtered on sintered glass The cake is washed with 2 times 50 cm3 of filtrate, dried under a hood and then in a vacuum oven (10 Pa) at a temperature in the region of 60 ° C. 23.4 g of 3-nitrophenylalanine hydrochloride in the form of white crystals are obtained. The reaction mixture was stirred at 222 ° C. 2 - [(Acetylamino) -2- (3-nitrobenzyl) malonate diethyl: 300 g of ethanol were added, with stirring under an inert atmosphere, 3.1 g of sodium. After total consumption of sodium, 29.1 g of diethyl acetamidomalonate are added and the mixture is then heated at a temperature of 78 ° C. for 20 minutes. A solution of 23 g of 3-nitrobenzyl chloride in 100 cm3 of ethanol is then poured and the heating is continued at this same temperature for 18 hours. The reaction mixture is cooled to a temperature in the region of 0 ° C. After stirring cold for 1 hour, the precipitate formed on sintered glass is filtered, the cake is washed with twice 50 cm 3 of filtrate and then 50 cm 3 of water. After drying in a ventilated hood and then in a vacuum oven (10Pa) at a temperature in the region of 50 ° C., 34 g of diethyl 2- (acetylamino) -2- (3-nitrobenzyl) malonate are obtained in the form of white crystals. melting at 156 ° C.

Example 3 (+ X4R, 5S) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

A suspension of 1.8 g of N - [(1R, 2S) -1-benzyl-2-hydroxypropyl] -7'-N-butyithiourea (diastereoisomer A) in 21 cm3 of 6N hydrochloric acid is heated to a temperature of close to 100 ° C for 6 hours. 10 cm3 of 6N hydrochloric acid are added again and the heating is continued for 6 hours. The reaction medium is filtered hot on sintered glass, the insoluble material is washed twice with 5 cm3 of hot 6N hydrochloric acid. The filtrate is cooled to a temperature in the region of 0 ° C., then 20 cm3 of water are added and finally made alkaline with 30 cm3 of 30% sodium hydroxide. It is extracted with 3 times 50 cm3 of dichloromethane. Organic phases. The combined layers are dried over sodium sulphate, filtered and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40.degree. 1 g of pink oil is obtained, which is purified by chromatography under argon pressure (50 kPa), on a desilice gel column (particle size 40-63 μm, diameter 3 cm, height 35 cm), eluting with -mixture of 90% dichloromethane / 10% methanol. The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of 40 ° C. 0.31 g of (+) - (4R, 5S) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of white crystals, melting at 90 ° C. [Spectrum of RM H (300 MHz, (CO 3) 2 SO d6 with addition of a few drops of CD3COODd4, δ in ppm): 1.31 (d, J = 7 Hz: 3H); 2.89 (dd, J = 14 and 7.5 Hz: 1H); 3.01 (dd, J = 14 and 7.5 Hz: 1H); 3.91 (mt: 1H); 4.41 (mt: 1H); from 7.15 to 7.40 (mt: 5H). Relative lasterochemistry in position 4 and 5 was validated by NOE effect. A strong response of methylene benzyl is noted after irradiation of methyl; (an20 - +29.6 +/- 0.8 in 0.5% methanol)]. JV - [(1R, 2S) -1-Benyl-2-hydroxypropyl] -N-7-butylthiourea: A solution of 12.9 g of a 75% / 25% mixture of the 2 (3R) diastereoisomers -3-amino-4-phenyl-2-butanol in 160 cm3 of ethanol, added with 9.50 cm3 of Zer-butylisothiocyanate is stirred at room temperature for 36 hours and then heated for 2 hours at a temperature of 60 ° C. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature of 40 ° C to give 20.8 g of a yellow oil. This oil is purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 40-63 μm, diameter 5 cm, height 50 cm), eluting with a mixture of dichloromethane 95% / ethyl acetate 5%. Fractions containing the diastereoisomer A are evaporated under reduced pressure (2 kPa) at a temperature of about 40 ° C. 1.95 g of 7V '- [(1R, 2S) -1-benzyl-2-hydroxypropyl] -2'-N-butylthiourea are obtained in the form of pale yellow crystals melting at 128 ° C. (NMR Spectrum). ÎH (250 MHz, (CD3) 2SO d6, δ in ppm): 0.96 (d, J = 7 Hz: 3H); 1.42 (s: 7.10 to 7.40 (mt, 6H), 7.44 (brs: 1H)] Concentrating under the same conditions the fractions corresponding to diastereoisomer B, 6.5 g of 2V are obtained. - [(1R, 2R) -1-Benzyl-2-hydroxypropyl] -A, -ter-2-butylthiourea as white crystals melting at 155 ° C [NMR Spectrum (250 MHz, (CD3) 2SO d6, δ in ppm) : 1.08 (d, J = 7

Hz: 3H); 1.39 (s: 9H); 2.80 (AB limit: 2H); 3.68 (mt: 1H); 4.42 (xnf: 1H); 4.78 (mf: 1H); 7.08 (d, J = 8.5 Hz: 1H); from 7.10 to 7.40 (mt: 6H). (3R) -3-Amino-4-phenyl-2-butanol: A solution of 19.3 g of ieri-butyl (1R) -1-benzyl-2 Hydroxypropylcarbamate in 160 cm of dioxane and 67 cm of 6.5 N dioxane hydrochloric acid are stirred at room temperature for 5 hours and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. A yellow oil is obtained which is The mixture is taken up in 50 cm3 of water and basified to a pH of about 10 with potassium carbonate and the mixture is extracted with ethyl acetate (3 × 100 cc) and the combined organic phases are dried over sodium sulfate, filtered and evaporated under reduced pressure. (2 kPa) at a temperature in the region of 40 ° C. 12.9 g of a 75% / 25% mixture of the two diastereomers A and B of (3R) -3-amino-4-phenyl-2 are obtained. butanol in the form of an orange oil [NMR Spectrum (300 MHz, (Cܳ) ₂SO d6, δ in ppm) A mixture of diastereoisomers: from 0.70 to 1.50 (mf spread: 2H) 1.0 8 (d, J - 6 Hz: 3H): 2.25 to 2.45 (mt: 1H); from 2.70 to 2.85 (mt: 2H); 3.44 (mt: 1H); from 4.25 to 4.75 (mf: 1H); from 7.10 to 7.35 (mt: 5H)]. 1-Butyl (1 R) -1-benzyl-2-hydroxypropylcarbamate: Under an inert atmosphere, a solution of 21 g of tert-bulyl (1 R) -1-benzyl-2-oxopropyl carbamate in 200 cm 3 of ethanol is cooled to a temperature of 10 ° C and then added by small fractions of 4.55 g of sodium borohydride. The temperature of the reaction medium is allowed to rise to room temperature with stirring, and then stirring is continued for 18 hours. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. to obtain white crystals which are taken up in 150 cm 3 of water. The mixture is left to stir for 2 hours at room temperature and is filtered on sintered glass. The cake is washed with 2 times 150cm3 of water. After drying overnight in a ventilated hood, 19.37 g of tert-butyl (1 R) -1-benzyl-2-hydroxypropylcarbamate are obtained in the form of white crystals melting at 127 ° C. [300 MHz NMR Spectrum]. MHz, (CD3) 2SO d6 with addition of a few drops ofCD3COOD d4, δ in ppm). There is a mixture of two diastereoisomers in the proportions 70/30: 1.04 and 1.10 (2d, J = 6 Hz: 3H); 1.29 and 1.32 (2s: 9H); 2.40 to 3.10 (mt: 2H); from 3.35 to 3.70 (mt: 2H); 6.40 and 6.54 (2d, J = 9 Hz: 1H); from 7.10 to 7.35 (mt: 5H)]. tert-Butyl (1 R) -1-benzyl-2-oxopropylcarbamate: A mixture, under atmosphere, of 26.7 g of tert-butyl (1 R) -1-benzyl-2- [methoxy (methyl) amino] -2- oxoethylcarbamate in 534 cm3 of dried sieved tetrahydrofuran 4 is cooled to a temperature in the region of 0 ° C. 87 cm 3 of a solution of 3 M methyl magnesium bromide in diethyl ether are then added over 45 minutes, followed by stirring for 1 hour at 0 ° C. and 18 hours at room temperature. The reaction medium is cooled to a temperature close to 0 ° C., then 55 cm 3 of 1N hydrochloric acid are added dropwise and the mixture is stirred for 30 minutes at this temperature. After filtration on celite, 200 cm3 of water is added to the filtrate which is then extracted with twice 200 cm3 of ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and then concentrated under reduced pressure (2 cfa) at a temperature in the region of 40.degree. 21.2 g of β-butyl (1R) -1-benzyl-2-oxopropyl caibamate are obtained in the form of yellow crystals melting at 59 ° C. [NMR Spectrum]. HJ (300 MHz, (CD3) 2SO d6, δ in ppm): 1.34 (s: 9H); 2.13 (s: 3H); 2.71 (dd, J = 14 and 10 Hz: 1H); 3.01 (dd, J = 14 and 5 Hz: 1H); 4.13 (mt: 1H); from 7.10 to 7.35 (mt: 6H)]. N-Butyl (1 R) -1-benzyl-2- [methoxy (methyl) amino] -2-oxoethylcarbamate: A solution, under an inert atmosphere, of 26.5 g of DN-Boc-phenylalanine and 22 cm of N -methylmorpholine in 300 cm3 of dichloromethane is cooled to a temperature of -15 ° C. 13 cm3 of isobutylchloroformate are then poured in and the mixture is stirred for 15 minutes. at this temperature. After addition of 10.14 g of chlor, Ο-dimethylhydroxylamine hydrochloride, the stirring is continued for 1 hour at a temperature of -15 ° C and then 3 hours at room temperature. The reaction medium is treated with 300 cm3 of water and then extracted twice with 200 cm3 of dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure (2 kPa) at a temperature in the region of 50 ° C. 32.2 g of an orange oil are obtained which is purified on a column of silica gel (particle size 40-63 μm, height 032 cm), eluting with a mixture of 97% dichloromethane / 3% methanol. After concentrating the fractions containing the expected product under reduced pressure (2 kPa) at a temperature in the region of 40 ° C., 26.7 g of tert-butyl (1 R) -1-benzyl-2- [methoxy (methyl) amino are obtained. ] -2-oxoethylcarbamate as a yellow oil [NMR spectrum] (250 MHz, (CD3) 2SO d6, δ in ppm): 1.32 (s: 9H); 2.72 (dd, J = 13.5 and 10 Hz: 1H); 2.86 (dd, J = 13.5 and 5 Hz: 1H); 3.12 (s: 3H); 3.74 (s wide: 3H); 4.55 (mt: 1H); from 7.10 to 7.35 (mt: 6H)]. 012286 39

Example 4 (+) - (4R, 5R) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

A suspension of 6.5 g of JV - [(1R, 2R) -1-benzyl-2-hydroxypropyl] -7H-di-tert-butylthiourea (diastereoisomer B) in 77 cm 3 of 6N hydrochloric acid is heated to a temperature of close to 100 ° C for 10 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. to give a yellow oil which is taken up in 100 cm 3 of water. This aqueous phase is washed with twice 50 cm3 of dichloromethane and is then alkalinized to a pH of 10 by adding 5 cm3 of concentrated sodium hydroxide. It is then extracted with 3 times 50 cm3 of dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 4.09 g of (+) - (4R, 5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of white crystals melting at 89 ° C. [Specter NMR (300MHz, (CD3) 2SO d6, δ in ppm): 1.22 (d, J = 7 Hz: 3H); 2.66 (dd, J = 13 and 7 Hz: 1H); 2.76 (dd, J = 13 and 7 Hz: 1H); 3.54 (mt: 1H); 3.95 (mt: 1H); from 5.60 to 6.45 (mf: 2H); from 7.10 to 7.40 (mt: 5H). Relative stereochemistry at positions 4 and 5 was validated by NOE. A strong response of proton H4 is noted after irradiation of ethyl; (ocd20 ~ +83.9 +/- 1.3 in 0.5% methanol)].

Example 5 (-) - (4R) -4- (3-Thienylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride

A mixture of 0.94 g of 7 - ((ez) -butyl) -N - [(1R) -2-hydroxy-1- (3-thienylmethyl) ethyl] thiourea in 9.2 cm 3 of 6N hydrochloric acid is heated. at a temperature close to 100 ° C with stirring for 3 hours and is then concentrated under reduced pressure (2 kPa) at a temperature of 40 ° C, A dalver oil is obtained which is taken up in 10 cm3 of acetone to give a sticky gum. Then 1.5 cm3 of ethanol is added, then 6 cm3 of diethyl ether are added dropwise with stirring. The crystals obtained are filtered on a sintered glass, washed with diethyl ether and then dried in the oven under vacuum (10 Pa) at a temperature of about 50.degree. 0.5 g of (-) - (4R) -4 - (3-thienylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine, hydrochloride are obtained in the form of gray crystals melting at152 ° C. C [NMR spectrum (400 MHz, (CD 2 SO d6, δ in ppm): 2.99 (mt: 2H); 3.26 (dd, J-11 and 5.5 Hz: 1H); 3.59 (dd, J = 11 and 8 Hz: 1H), 4.54 (mt: 1H), 7.10 (dd, J = 5.5 and 1 Hz: 1H), 7.38 (mt: 1H), 7.54 (dd, J = 5 and 3 Hz: 1H), 9.15 to 10.55 (mw spread: 3H), (aD20 = -4.3 +/- 0.5 in 0.5% methanol). (ieri-butyl) -TH - [(1R) -2-hydroxy-1- (3-thienylmethyl) ethyl] thiourea: A suspension of 0.9 g of (2R) -2-amino-3- (3-thienyl) 1-Propanol, hydrochloride in 9 cm3 of ethanol, stirred under an inert atmosphere, is treated with tet-butylisothiocyanate (0.9 cc) and triethylamine (0.82 cc) after stirring for 66 hours at room temperature. under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The thick brown oil obtained is taken up in 6 cm 3 of water and then extracted with twice 12 cm 3 of ethyl acetate, the organic phase is filtered through celite and then washed with 2 times 4 cm3 of a saturated aqueous solution of sodium chloride, chée over magnesium sulfate and evaporated under reduced pressure (2 kPa) at a temperature of 40 ° C. A brown oil is obtained which crystallizes rapidly in the cold and is dried in the oven in vacuo (10 Pa) at a temperature of about 48 ° C to give 0.97 g of N- (ierf-butyl) -M - [(1R). 2-hydroxy-1- (3-thienylmethyl) ethyl] thiourea as a beige colored solid melting at 109 ° C. [NMR spectrum] * H (400 MHz, (CD3) 2SO d6, δ in ppm): 1.43 (s: 9H); 2.84 (mt: 2H); 3.38 (mt: 2H); 4.42 (mf: 1H); 4.86 (t wide, J = 4.5 Hz: 1H); 7.04 (broad d, J = 5 Hz: 1H); from 7.10 to 7.20 (mt: 2H); 7.25 (s-broad: 1H); 7.46 (dd, J = 5 and 3 Hz: 1H)]. (2R) -2-Amino-3- (3-thienyl) -1-propanol hydrochloride: A solution of 1.4 g of N - [(1R) -2-hydroxy-1- (3-thienylmethyl) ethyl] acetamide in 17.6 cm3 of 6N aqueous hydrochloric acid is heated with stirring at a temperature of about 100 ° C for 2 hours. The reaction mixture is then concentrated under reduced pressure (2 kPa) at a temperature of 40 ° C to give a greenish oil which crystallizes in 60 cm3 of acetone. The crystals are filtered on sintered glass, washed with acetone and then dried in the oven under vacuum (10 Pa) at a temperature of 50 ° C. 0.92 g of (2R) -2-amino-3- (3-thienyl) -1-propanol, hydrochloride, are obtained in the form of an off-white solid (NMR Spectrum). (400 MHz, (CD3) 2SO d6, δ enppm): 2.93 (mt: 2H); from 3.25 to 3.50 (mt: 2H); 3.53 (broad, J = 11 Hz: 1H); 5.37 (mf: 1H); 7.07 (broad d, 5 Hz: 1H); 7.35 (mt: 1H); 7.53 (dd, J = 5 and 3 Hz: 1H), 8.18 (mf: 3H), JV - [(1R) -2-hydroxy-1- (3-thienylmethyl) ethyl] acetamide: A solution of 2.15 g of ethyl (2R) -2- (acetylamino) -3- (3-thienyl) propanoate in 24 cm3 of ethanol, stirred in an inert atmosphere, is brought to a temperature of 20 ° C. 0 5 g of sodium hydrobromide are then stirred into the reaction medium, which is gently stirred for 24 hours at room temperature, 0.2 g of sodium borohydride are added and the stirring is continued for 24 hours after evaporation of the reactional mixture under pressure. reduced (2kPa) at a temperature of 40 ° C, obtains a solid residue which is taken up in 30 cm3 of water is extracted with twice 100 cm3 of ethyl acetate then the organic phase is dried over magnesium sulfate and evaporated under reduced pressure (2 kPa) at a temperature of 40 ° C to give an off-white solid which is dried in the vacuum oven (lOPa) at a nearby temperature At 48 ° C., 1.4 g of W - [(1R) -2-hydroxy-1- (3-thienylmethyl) ethyl] acetamide are obtained in the form of an off-white solid which melts at approximately 105 ° C. pasty [NMR spectrum (400 MHz, (CD 2 SOd 6, -5 ppm): 1.78 (s: 3H), 2.64 (dd, J = 14 and 8 Hz: 1H), 2.87 (dd, J = 14 and 5.5 Hz: 1H), 3.20 to 3.40 (mt: 2H), 3.90 (mt: 1H), 4.76 (t, J = 5.5 Hz: 1H), 6.99. (dd, J = 5 and 1 Hz: 1H), 7.16 (dd, J = 3 and 1 Hz: 1H), 7.43 (dd, J = 5 and 3 Hz: 1H), 7.70 (dd, J = 5 and 1 Hz: 1H); , J = 8.5 Hz: 1H], (2R) -2- (acetylamino) -3- (3-thienyl) propanoate: A solution of 2.41 g of 2- (acetylamino) -3- ( Ethyl acetate (3-thienyl) propanoate in 17 cm3 of inert subatmosphere stirred acetonitrile is added with 3.95 g of ammonium hydrogencarbonate and 35 cm 3 of deionized water, 0.017 g of α-chymotrypsin type Π, the pH of the reaction medium is then close to 8. The mixture is stirred for 1 hour at room temperature and then added, after having observed that the pH was maintained at 8.0.017 g of α-chymoteypsin type Π. stirring time, the pH is constant, is introduced again 0.017 g of a-chymotrypsin type H and stirring is continued moela nge reaction for 19 hours at room temperature. The acetonitrile is evaporated under reduced pressure (2 kPa) at a temperature in the region of 33 ° C. and 25 cm3 of ethyl acetate are added to the residual aqueous phase. The emulsionobtained on celite is filtered and the aqueous phase is then extracted with twice 25 cm.sup.3 of ethyl acetate. The organic phases are combined, washed with twice 15 cm3 of a sodium carbonate solution and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The solid residue is then dried in the oven under vacuum (lOPa) at room temperature. 1.1 g of ethyl (2R) -2- (acetylamino) -3- (3-thienyl) propanoate are obtained in the form of a beige solid which melts at about 75.degree. 2- (Ethyl acetylamino) -3- (3-thienyl) propanoate: A pale yellow solution of 7.7 g of diethyl 2- (acetylamino) -2- (3-thienylmethyl) malonate in 62 cm3 of dimethylformamide, stirred under stirring. inert atmosphere is added at once 9.83 g of lithium iodide and then heated in; a temperature oil bath of about 128 ° C for 19 hours. 6.6 g of lithium iodide are added and the heating is continued for 5 hours. The reaction medium is then evaporated under reduced pressure (2.4 kPa) at a temperature in the region of 55 ° C. The residual brown oil is taken up in 180 cm 3 of water and is extracted with 4 times 60 cm 3 of ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution (30 cc), dried over magnesium sulphate and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 62 ° C. to give 5.34 g of a bromine oil which crystallize cold. The crystals are taken up in 40 cm 3 of petroleum ether, ground in a mortar and then filtered on sintered glass and dried in the oven under vacuum (lOPa) at room temperature. 4.9 g of ethyl 2- (acetylamino) -3- (3-thienyl) propanoate are obtained in the form of an off-white solid melting at about 60 ° C (NMR Spectrum). iH (400 MHz, (CD3) 2SO d6, δ in ppm): 1.14 (t, J = 7Hz: 3H); 1.84 (s: 3H); 2.93 (dd, J = 14 and 9 Hz: 1H); 3.03 (dd, J = 14 and 5.5 Hz: 1H); 4.06 (mt: 2H); 4.44 (mt: 1H); 7.02 (dd, J = 5 and 1 Hz: 1H); 7.24 (mt: 1H); 7.45 (dd, J = 5 and 3 Hz: 1H); 8.31 (d, J = 8 Hz: 1H) 2- (acetylamino) -2- (3-thienylmethyl) malonate diethyl: To 115 cm3 of ethanol absolute, 1.54 g are added with stirring under an inert atmosphere. After total consumption of the sodium, 14.55 g of diethyl acetamidomalonate are added and the mixture is heated at a temperature of 78 ° C. for 20 minutes and a solution of 16.5 g of 3- (bromomethyl) -thiophene is then poured. freshly prepared in 50 cm 3 of ethanol and heating is continued at this same temperature for 19 hours The reaction medium, which contains a white insoluble material, is cooled to a temperature in the region of 0 ° C. and then filtered on a sintered glass. The crystals are taken up in water (100 cc), filtered again, washed with petroleum ether and dried under a hood at room temperature. 1.45 g of 2- (acetylamino) -2- (3-thienyl) are obtained. methyl) diethyl malonate as a white solid melting at about 92 ° C. After evaporation in ambient air of the solvent dewatering, the residue is taken up in 150 cm3 of water and then is filtered on sintered glass. The yellowish solution obtained is washed with 50 cm3 of water and then dissolved in 25 cm3 of ethanol absolute and then crystallized by addition of 25 cm3 of water. After filtration, washing with 3 times 30 cm3 of petroleum ether and then drying under a hood at room temperature, 6.57 g of diethyl 2- (acetylamino) -2- (3-thienylmethyl) malonate are obtained in the form of a solid. white color melting at about 92 C [NMR Spectrum] iH (300 MHz, (CD3) 2SO d6, δ in ppm): 1.18 (t, J = 7 Hz: 6H); 1.98 (s: 3H); 3.50 (s: 2H); 4.16 (q, J = 7 Hz: 4H); 6.80 (broad d, J = 5 Hz: 1H); 7.14 (brs: 1H); 7.46 (dd, J = 5 and 3 Hz: 1H); 8.20 (s wide: 1H)].

3- (bromomethyl) -thiophene can be prepared according to J. GOURIER and P.CANNONE; Bull. Soc. Chim. Fr. 1971,3299-3306. s

A 44 012286

Example 6 [3- (2-amino-4,5-dihydro-triazol-4-yl) -phenyl] - (1-imino-ethyl) amine To a stirred solution of 0.14 g of 4- ( 3-aminophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine in 15 cm 3 of ethanol is added under an inert atmosphere and at a temperature of 0 ° C approximately 0.15 g of benzylethanimidothioate hydrochloride, then 5 cm3 of ethanol. The mixture is stirred for 1 hour at about 0 ° C. and then for 2 hours at a temperature in the region of 20 ° C. 0.030 g of benzyl ethanimidothioate is added to determine the reaction, then the mixture is brought to a temperature of 45 ° C for 24 hours. The reaction medium is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in 30 cm3 of water, the washed solution with 30 cm3 of dichlorométhàne. The aqueous solution is concentrated under the preceding conditions, then the solid obtained is triturated in diethyl ether, filtered, air dried, purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63μ, mass 63 g ) eluting with a mixture of dichloromethane-methanol-ammonia (12/3 / 0.5 by volume). The fractions containing the expected product are collected. These are combined and evaporated under reduced pressure (5 kPa) at a temperature of 40 ° C. 0.100 g of [3- (2-amino-4,5-dihydro-thiazol-4-yl) -phenyl] - (1-imino-ethyl) -amine is obtained in the form of a white solid melting at 180 ° C. [NMR spectrum * H (250MHz, (CDshSO d6 with addition of drops of CD3COOD d4, 6 in ppm): 2.28 (mf: 3H), 3.18 (dd, J = 12.5 and 8.5 Hz: 1H) 3.80 (dd, J = 12.5 and 8.5 Hz: 1H), 5.30 (t, J = 8.5 Hz: 1H), 7.21 (dd, J = 8.5 Hz: 1H), 7.27 (s wide: 1H), 7.36 (broad d, J = 8.5 Hz: 1H), 7.49 (broad t, J = 8.5: Hz: 1H).

The benzylethanimidothioate hydrochloride can be obtained by application of the method described in the patent WO 96/19440. 4- (3-Aminophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine: To a suspension of 2.4 g of 4- (3-nitrophenyl) -4,5-dihydro hydrochloride 1, 3-thiazol-2-ylamine in 50 cm3 of 85% by volume acetic acid, 3 g of powdered zinc are added at a temperature in the region of 20 ° C. with stirring. After stirring for 20 minutes at room temperature, the reaction medium is filtered; the cake is washed with 10 cm3 of water, and the filtrate is concentrated under reduced pressure (5 fcPa) at a temperature in the region of 50 ° C.The residue obtained is taken up in methanol and then diethyl ether, concentrated in the same conditions than previously. This operation is repeated a second time. The product obtained is taken up in 100 cm3 of acetonitrile, filtered. The filtrate is concentrated as above, taken up with 60 cm of water. The insoluble matter is filtered, while the filtrate is made alkaline by addition of 7 cm 3 of an aqueous solution of sodium hydroxide. The insoluble matter is separated by filtration, and the filtrate is again concentrated as above, taken up in 40 cm of carbon dioxide. a mixture of dichloromethane-methanol-ammonia (40/5 / 0.5 by volume). The insoluble material is filtered and the filtrate is concentrated as before. 4.2 g of a yellow oil are obtained which is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63 μ, 100 g of silica), eluting by a mixture of dichloromethane-methanol-ammonia (40/5 / 0.5 by volume). The fractions containing the product are combined and then concentrated (5 kPa) at a temperature in the region of 40 ° C. 0.73 g of 4- (3-aminophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine is obtained as a yellow solid, mp 152 ° C.

4 - (3-Nitrophenyl) -4,4-dihydro-1,3-thiazol-2-ylamine hydrochloride: The procedure is as in Example 2, from 4.77 g of N- (tert-butyl) -N '- [2-hydroxy-1- (3-nitrophenyl) ethyl] thiourea, 44 cm3 of 6N aqueous hydrochloric acid which is heated to a temperature of 100 ° C for 2h30. After identical treatment, 4.1 g of 4- (3-nitrophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of a cream-colored solid, mp 232 ° C. ° C. N - ([? - Butyl) -N '- [2-hydroxy-1- (3-nitrophenyl) ethyl] thiourea: The procedure is as in Example 2 starting from 5.1 g of 2-amino-2- (3-nitrophenyl) -1-ethanol in 170 cm 3 of ethanol added with 85 cm 3 of dichloromethane and 4.6 cm 3 of tert-butyl isothiocyanate at a temperature of 20 ° C for 3 days, then at a temperature close to 60 ° C for 7 hours. After an addition

0.35 cm3 of isothiocyanate of ier-butyl ester and 16 hours at a temperature of about 60 ° C, by an identical treatment is obtained 5.7 g of N- (tert-butyl) -N'- [2-hydroxy-1- (3-nitrophenyl) ethyl] thiourea as an ocher-colored solid melting at 162 ° C. 2-Amino-2- (3-nitrophenyl) -1-ethanol: The procedure is as in Example 2 starting from 1 g of ethyl 3-nitrophenylglycinate in 20 cm3 of ethanol with 0.255 g of sodium hydrobromide and 20 hours. at a temperature of 20 ° C. After identical treatment, 0.200 g of 2-amino-2- (3-nitrophenyl) -1-ethanol is obtained, in the form of an oily yellow paste (R = 0.18 in a 90/10 dichloromethane-methanol mixture). in volumes, on silica plate Merck 60F254R). Ethyl 3-nitrophenylglycinate: 2 g of 3-nitrophenylglycine are heated for 20 hours with stirring at a temperature in the region of 100 ° C. in 100 cm3 of ethanol absolute, supplemented with 20 cm3 of 6.5N hydrochloric ethanol. The suspension is filtered at a temperature in the region of 50 ° C .; the filtrate is concentrated under reduced pressure (5 fcPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in water and extracted with approximately 100 cm3 of ethyl acetate. The aqueous phase is rendered alkaline by the addition of sodium carbonate until a pH of about 10 is obtained.

The medium is extracted with ethyl acetate; the combined extracts are washed with an aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure (5 kPa) at 40 ° C. 1 g of ethyl 3-nitrophenylglycinate is obtained in the form of a yellow-colored oil (R = 0.38 in a dichloromethane-methanol mixture, 95/5 by volume, on a silica plateMerck 60F254R). 3-NItrophenylglycine: To a mixture of 1.51 g of D - (-) - alpha phenylglycine in 6 cm3 of 95% sulfuric acid, 1.01 g is slowly added at a temperature in the region of 0 ° C., with stirring. of potassium nitrate, then the temperature is allowed to rise to around 20 ° C. The resulting solution is poured into 30 cm3 of ice water and rerun at pH 7 by addition of 18.5 cm3 of 10N sodium hydroxide at a lower temperature at 5 ° C. The mixture is stirred for 2 hours and then filtered. The cake obtained is washed twice with 50 cm3 of water and then dried. 0.60 g of 3-nitrophenylglycine is obtained, which is a cream-colored solid and melts at 230.degree.

Example 7

(+) - (4R) -Benzyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride

The procedure is as in Example 2 starting from 2 g of N- (ier-butyl) -N '- [(1R) -2-hydroxy-1- (phenylmethyl) ethyl] thiourea, 20 cm3 of aqueous hydrochloric acid. The reaction lasts for 1 h 30. After cooling the reaction mass to a temperature in the region of 0 ° C., the solution is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. To the oil obtained crystallization is initiated. Addition of diethyl ether The resulting precipitate is filtered off, washed with twice 10 cm of diethyl ether and then dried under reduced pressure (10 Pa) at a similar temperature.

At 60 ° C. The product is purified by taking it into 100 cm 3 of dichloromethane under stirring for 30 minutes. After filtration of the suspension, the cake is washed twice with 10 cm 3 of dichloromethane and then dried under the same conditions as above. 1.1 g of (+) - (4R) -4-phenylmethyl-4,5-hydrochloride are obtained. dihydro-1,3-thiazol-2-ylamine, as a white solid melting at 168 ° C. (aD20 = +8.7 +/- 0.3 in 1% methanol). N - (1-Erid-Butyl) -N '- [(1R) -2-hydroxy-1- (benzyl) ethyl] thiourea: The procedure is as in Example 2 starting from 5 g of (R) - (+) 2- amino-3-phenyl-1-propanol in 50 cm3 of ethanol and 5.7 g of Fe / V-butyl isothiocyanate at a temperature of 20 ° C for 16 hours. After identical treatment, 8.7 g of N- (1-yl-butyl) -N '- [(1R) -2-hydroxy-1- (phenylmethyl) ethyl] thiourea are obtained in the form of a white solid at 107 ° C. . 48 012286

Example 8

(+) - (4R) -4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride

The procedure is as in Example 2 starting from 2.31 g of N- (f -zn-butyl) -N '- [(1R) -2-hydroxy-1- (3-carboxybenzyl) ethyl] thiourea in 25 cm 3 6N hydrochloric acid for 18 hours After concentrating the reaction mixture under reduced pressure (5 kPa) at room temperature. a temperature close to 55 ° C, the residue is taken up in 20 cm3 of acetone, and then again concentrated under the conditions above. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a desilic gel column (particle size 40-63μ, silica mass 100 g), eluting with a 20% chloroform-methanol-ammonia mixture (12 / 6/1 by volume) and collecting fractions of 30 cm3. Fractions 16 to 38 are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The solid obtained is dissolved in 10 cm 3 of 6N aqueous hydrochloric acid and then concentrated as previously. After taking up the residue obtained with 10 cm 3 of acetone, the resulting insoluble material is filtered off; the filtrate is concentrated as above. A solid is obtained which is dried for 5 hours in an oven at 40 ° C under reduced pressure (8 Pa). 0.650 g of (+) - (4R) -4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of a beige-colored solid which melts at 151 ° C, (yr = +13.4 +/- 0.6 in 0.5% methanol). N - (/ er-Butyl) -N '- [(1R) -2-hydroxy-1- (3-carboxybenzyl) ethyl] thiourea: The procedure is as in Example 2 starting from 1.82 g of hydrochloride. (2R) -2-Amino-3- (3-carboxyphenyl) -1-propanol, in 20 cc of ethanol, 4.2 cc of triethylamine and 17 cc of tertiary butyl isothiocyanate. After 21 hours of heating at a temperature of about 60 ° C. and identical treatment, 2.31 g of N- (ieri-butyl) -N '- [(1R) -2-hydroxy-1-yl) are obtained. carboxybenzyl) ethyl] thiourea as a light brown meringue (R = 0.33 in a mixture of chloroform-methanol-ammonia 12/6/1 by volume, on a silica plate Merck 60F254 *).

I 49 012286

(2R) -2-amino-3- (3-carboxyphenyl) -1-propanol hydrochloride: Example 2 is prepared from 1.96 g of N - [(1R) -2-hydroxy-1-yl). (3-carboxybenzyl) ethyl] acetamide in 14 cm3 of aqueous hydrochloric acid 6Heated at a temperature of about 100 ° C for 17 hours. After treatment, 2.16 g of (2R) -2-amino-3- (3-carboxyphenyl) -1-propanol hydrochloride are obtained in the form of a white solid which melts at 194 ° C. N - [(1R) -2-Hydroxy-1- (3-cyanobenzyl) ethyl] acetamide: The procedure is as in Example 2 starting from 3.3 g (2R) -2-acetylamino-3- (3-cyanophenyl) ) ethyl propanoate and 1.23 g of sodium borohydride in 50 cm3 of ethanol operating at a temperature of -30 ° C, after 16 hours of stirring at a temperature of 20 ° C, the reaction medium is evaporated under reduced pressure (5 kPa) at a temperature of about 45 ° C, and the resulting residue is stirred in a mixture of 100 cm3 of water and 100 cm3 of ethyl acetate. The organic phase is decanted while the aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and then washed with twice 50 cm3 of water, dried over magnesium sulphate, filtered and evaporated under reduced pressure (5 kPa) at a temperature in the region of 45 ° C. 2.13 g of N - [(1R) -2-hydroxy-1- (3-cyanobenzyl) ethyl] acetamide are obtained in the form of a white solid (an20 - +7.5 +/- 0.6 in 0.5% methanol). (2R) -2-ethyl acetylamino-3- (3-cyanophenyl) propanoate: The procedure is as in Example 2 starting from 11.39 g of (2RS) -2-acetylamino-3- (3-cyanophenyl) ethyl propanoate, 17.39 g of ammonium hydrogencarbonate, 0.1 g of α-chymotrypsin in 200 cm 3 of water and 70 cm 3 of acetonitrile. After stirring for 24 hours at a temperature of 20 ° C., and identical treatment, 5.40 g of ethyl (2R) -2-acetylamino-3- (3-cyanophenyl) propanoate are obtained in the form of a beige solid, (R = 0.76 in a mixture of n-butanol-acetic acid-water, 40/10/20 by volume, Merck silica overhang 60F254R). (2RS) -2-ethyl acetylamino-3- (3-cyanophenyl) propanoate: Example 5 is prepared from 14.9 g of 2-acetylamino-2- (3-cyanobenzyl) malonate. ethyl, 30 g anhydrous lithium iodide, 150 cm3 dry dimethylformamide. After stirring for 5 hours at a temperature in the region of 150 ° C., the reaction mass is cooled to room temperature. 1500 cm3 of water are added and the mixture is extracted with 3 times 300 cm3 of ethyl acetate. The extracts are combined, dried over magnesium sulphate, filtered, concentrated under reduced pressure (5 kPa) at a temperature of 45 ° C. After drying in an oven at a temperature in the region of 40 ° C. under reduced pressure (10 Pa), 11.39 g of ethyl (2RS) -2-acetylamino-3- (3-cyanophenyl) propanoate are obtained in the form of dichloromethane. a beige colored paste, (R = 0.51 in a mixture of ethyl acetate-cyclohexane, 90/10 by volume, on a Merck 60F254 * silica plate). Ethyl 2-acetylamino-2- (3-cyanobenzyl) malonate: The procedure is as in Example 5 starting from 27.7 g of diethyl acetamidomalonate, 25 g of 3-cyanobenzyl bromide, 3.2 g. of sodium, in 400 cm3 of absolute ethanol. After treatment identical, the cooled reaction mass is filtered, the cake washed with 2 times 50 cm3 of ethanol then with 2 times 50 cm3 of water. After drying in an oven under reduced pressure (10 Pa) at a temperature in the region of 40 ° C., 21.98 g of a white powder are obtained.

The filtrate is evaporated under reduced pressure (5 kPa) at a temperature in the region of 50 ° C. to give a meringue which is taken up in 100 cm 3 of water and extracted with ethyl acetate (100 cc) and then extracted with ethyl acetate (100 cc). 2 times 50 cm3 of the same solvent. The extracts sontréunis, washed with 2 times 50 cm3 of water, dried over magnesium sulfate, filtered, evaporated under reduced pressure (5 kPa) at a temperature of 45 ° C. The residue obtained is taken up in 20 cm3 of ethanol. The resulting crystals are filtered off, washed with ethanol and dried in an oven under reduced pressure (10 Pa) at a temperature of 40.degree. The two streams are combined and 31.94 g of ethyl 2-acetylamino-2- (3-cyanobenzyl) malonate are obtained in the form of a white powder melting at 138 ° C. 51 012286

Example 9

(+) - (4R) -4- (4-Aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylaniine dihydrochloride

The procedure is as in Example 1 starting from 5.9 g of benzyl (5R) -5 - {[(tert-butylamino) carbothioyl] ammo} -6-hydroxyhexylcarbamal in 40 cm3 of 6N aqueous hydrochloric acid. a temperature close to 100 ° C for 3 hours. After concentrating the reaction medium under reduced pressure (5 KPa) at a temperature in the region of 50 ° C., the residue obtained is taken up in ethanol and again concentrated under the conditions of the above. The paste obtained crystallizes partrituration in a mixture of ethanol-methanol (8/2 by volume). The crystals are filtered, washed with acetonitrile, air dried. 1.3 g of (+) - (4R) -4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride are obtained in the form of a white solid, m.p. ° C, (α = 20 + 16.2 +/- 0.7 in 0.5% methanol). Benzyl (5R) -5- {[(ter-Butylamino) carbothioyl] amino} -6-hydroxyhexylcarbamate To a stirred solution of (2R) -6 - {[(benzyloxy) caibonyl] amino (12.7 g) Ethyl 2 - {[(tert-butylamino) carbothioyl] amino} hexanoate in 130 cm3 of ethanol and 65 cm3 of tetrahydrofuran, under an inert atmosphere and cooled to 0 to 5 ° C, is added 1.78 g of lithium chloride then 1.6 g of sodium borohydride. After stirring for 16 hours at a temperature in the region of 20 ° C., 0.4 g of hydrobromide is added, and the mixture is brought to approximately 80 ° C. for 4 hours. The milieueactionnal is filtered, the cake is washed with ethanol. The filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., and the residue obtained is taken up in a mixture of dichloromethane-ethyl acetate (85/15 by volume), left cold at about 5 ° C. . The crystallized product is drained, purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63μ, silica mass 600 g), eluting with a mixture of dichloromethane-ethyl acetate (85/15 by volume). Fractions containing the expected product are collected. These are combined and then concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 6.9 g of benzyl (5R) -5 - {[(tert-butylamino) carbothioyl] amino} -6-hydroxyhexylcarbamate are obtained in the form of a colorless oil (an20 = +24.0 +/- 0.8 in 0.5% methanol). (2R) -6 - {[(Benzyloxy) carbonyl] amino} -2 - {[(tert-butylamino) carbothioyl] amino} hexanoate ethyl: The procedure is as in Example 2 from 7.4 g of (2R) -2-amino-6 - {[(benzyloxy) carbonyl] amino} hexanoate with 5 cm3 of t-butyl isothiocyanate in 200 cm3 of anhydrous ethanol at a temperature of 20 ° C for 20 hours . The reaction is completed by addition of 1 cm 3 of isothiocyanate and heating for 2 hours at a temperature of about 80 ° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in ether, concentrated again as in the previous conditions. 13 g of ethyl (2R) -6 - {[(benzyloxy) carbonyl] amino} -2 - {[(tert-butylamino) carbothioyl] amino} hexanoate are obtained in the form of a colorless oil, (an = -12, 5 +/- 0.5 in 0.5% methanol). (2R) -2-Amino-6 - {[(benzyloxy) carbonyl] amino} ethyl hexanoate: A suspension of 7.9 g of (2R) -2-amino-6 - {[(benzyloxy) carbonyl) acid ] amino} hexanoic acid (Νε-CBZ-D-Lysine) in 120 cm3 of anhydrous ethanol cooled to a temperature of about -25 ° C., 3.9 cm3 of methionyl chloride are added with stirring. The mixture is stirred for 3 hours at this temperature and then allowed to come to about 20 ° C. After standing for 3 days, the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in 200 cm3 of ethyl acetate and the resulting solution is washed with an aqueous solution of sodium carbonate, then an aqueous solution of sodium chloride. The organic solution is dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 7.4 g of ethyl (2R) -2-amino-6 - {[(benzyloxy) carbonyl] amino} hexanoate are obtained in the form of a pale yellow-colored oil (cto20 = -11.7 +). 0.6% in 0.5% methanol). 53 012286

Example 10

(-) - (4S) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride

The procedure is as in Example 2 starting from 6.4 g of N- (tert-butyl) -N '- [(1S) -2-hydroxy-1 "(3-nitrobenzyl) ethyl] thiourea in 80 cm 3 of 6N aqueous hydrochloric acid. The heating time is 7 hours. The product is isolated in an identical manner and then purified by chromatography under an argon pressure of 80 kPa, on a column of silica gel (particle size 40-63 μ, diameter 3.5 cm, height 30 cm) eluting with a mixture dichloromethane-methanol (95/5 by volume). Fractions corresponding to the expected product are collected and collected and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 3.90 g of (-) - (4S) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained, in the form of a white solid melting at 220 ° C. C (an20 = -18.4 +/- 0.5 in 0.5% methanol). N- (Zert-Butyl) -N '- [(1S) -2-hydroxy-1- (3-nitrobenzyl) ethyl] thiourea: The procedure is as in Example 2 starting from 5.65 g of hydrochloride. (2S) -2-amino-3- (3-nitrophenyl) -1-propanol, 3.7 cm3 of isothiocyanate of tert-butyl, 3.41 cm3 of triethylamine in 60 cm3 of ethanol. After stirring for 3 days at a temperature in the region of 20 ° C. and then heating for 30 minutes at a temperature in the region of 60 ° C., 3.7 cm 3 of tertiary butyl isothiocyanate are added to the reaction medium, followed by further heating. hours at the same temperature. After identical treatment, 6.45 g of N- (t-butyl) -N '- [(1S) -2-hydroxy-1- (3-nitrobenzyl) ethyl] thiourea are obtained in the form of a meringue of yellow color, (R -0.61 in a mixture of dichloromethane-methanol-ammonia 40/5 / 0.5 by volume, silica plateMerck 60F254R). (2S) -2-Amino-3- (3-nitrophenyl) -1-propanol hydrochloride: The procedure is as in Example 2 starting from 5.8 g of N - [(1S) -2-hydroxy- 1- (3-nitrobenzyl) ethyl] acetamide in 60 cm 3 of 6N aqueous hydrochloric acid

J; at 54 ° C. for 10 hours at a temperature in the region of 100 ° C. After cooling the medium, the precipitate is filtered and then washed with 30 cm3 of acetone, 3 times 50 cm3 of ether, dried in an oven under reduced pressure (10 Pa) at a temperature of 60 ° C. The filtrate is concentrated under reduced pressure (5 kPa) at about 50 ° C. The residue obtained is taken up in 30 cm3 of diethyl ether, the crystals filtered, washed with twice 30 cm3 of ether, dried in an oven under the same conditions as above. The 2 crystallized jets sontréunis. 5.65 g of (2S) -2-amino-3- (3-nitrophenyl) -1-propanol hydrochloride are obtained in the form of a beige solid melting at 188 ° C. N - [(1S) -2-Hydroxy-1- (3-nitrobenzyl) ethyl] acetamide: The procedure is as in Example 2 starting from 7.15 g of (2S) -2- (acetylamino) - 3- (3-nitrophenyl) propanoateethyl, 1.46 g of sodium borohydride in 70 cm 3 of ethanol. By an identical treatment, 5.8 g of N - [(1S) -2-hydroxy-1- (3-nitrobenzyl) ethyl] acetamide are obtained in the form of a white solid melting at 131 ° C.

Ethyl (2S) -2- (acetylamino) -3- (3-nitrophenyl) propanoate can be prepared according to PIVIER et al. J. Med. Chem. (1995), 2658.

Example 11 (-) - (4S, 5S) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

The procedure is as in Example 3 starting from 3.9 g of the diastereoisomer A of N- (z'ezt-butyl) -N '- ((1S) -1-benzyl-2-hydroxypropyl) thiourea in 46 cc of d 6N aqueous hydrochloric acid. After heating for 5 hours at a temperature in the region of 100 ° C., the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 50 ° C. The oil obtained is dissolved in 50 cm 3 of water; the solution is washed with twice 50 cm3 of dichloromethane. The aqueous phase is made alkaline by addition of 3 cm3 of 30% sodium hydroxide solution and then extracted with 3 times 50 cm3 of dichloromethane. The organic extracts are combined and dried over sodium sulfate. After filtration and concentration under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., 2.5 g of (-) - (4S, 5S) -4-benzyl-5-methyl-4,5-diol are obtained. dihydro-1,3-thiazol-2-ylamine, in the form of a white solid melting at 89 ° C., (isomerretrans), (d20 - -87.3 +/- 1.3 in 0.5% methanol) ). N- (tert-Butyl) -N '- ((1S) -1-benzyl-2-hydroxypropyl) thiourea: The procedure is as in Example 3 starting from 9.5 g of (3S) -3-amino-4 -phenyl-2-butanol in 80 cm3 of ethanol and in the presence of 7.86 cm3 of isZi-butyl isothiocyanate. After stirring for 3 days at a temperature in the region of 20 ° C., and identical treatment, 15.9 g of an oil are obtained which is purified by chromatography under argon pressure (50 KPa), on a column of silica gel (particle size 40-63μ, diameter 5 cm, silica height 38 cm), eluting with a mixture of dichloromethane-ethyl acetate (95/5 by volume). The fractions containing the diastereoisomer A are combined and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 3.98 g of N- (Zero-butyl) -N '- ((1S) -1-benzyl-2-hydroxypropyl) thiourea diastereoisomer A are obtained in the form of a white solid, mp 156 ° C. Encompassing under the same conditions the fractions corresponding to diastereoisomer B, 0.72 g of N- (zerZ-butyl) -N '- ((1S) -1-benzyl-2-hydroxypropyl) thiourea diastereoisomer B are obtained, in the form of a yellow solid melting at 116 ° C. (3S) -3-amino-4-phenyl-2-butanol: The procedure is as in Example 3 starting from 17.6 g of (1S) -1-benzyl-2-hydroxypropylcarbamate ZerZ-butyl in 145 cm3 of Dioxane and 61 cm3 of 6.5N hydrochloric dioxane, with stirring for 16 hours at a temperature in the region of 20 ° C. By identical treatment, 9.56 g of (3S) -3-amino-4-phenyl-2-butanol is obtained in the form of an orange-colored oil which is a mixture of the two diastereoisomers (80/20), . (R = 0.25 in a mixture of dichloromethane-methanol-ammonia 40/5 / 0.5 by volume, on silica plate Merck 60F254R). (Z) 2-hydroxypropylcarbamate (1S) -1-benzyl-2-hydroxypropylcarbamate: The procedure is as in Example 3 starting from 2.66 g of (1S) -1-benzyl-2-oxopropylcarbamate of Zez'Z-butyl in 25 cc. of ethanol, with 0.58 g of sodium borohydride. After 4:30 to a temperature of 20 ° C, the reaction medium is treated identically. 2.7 g of ZerZ-butyl (1S) -1-benzyl-2-hydroxypropylcarbamate are obtained in the form of a white solid melting at 125 ° C., a mixture of the two diastereoisomers (70/30). (2S) -1-Benzyl-2-oxopropylcarbamate Zer-2-butyl: The procedure is as in Example 3 starting from 5 g of (1S) -1-benzyl-2- [methoxy (methyl) amino] -2 -Zero-butyloxoethylcarbamate, 16 cm3 of an ethereal solution of demethyl magnesium bromide, and 100 cm3 of anhydrous tetrahydrofuran. After the reaction is complete, the reaction medium is stirred for 18 hours at a temperature in the region of 20 ° C.

After identical treatment, 3.91 g of an orange oil are obtained which is purified

Z 10 by atmospheric pressure chromatography on a column of silica gel (particle size 63-200μ, diameter 3.5 cm, height 20 cm), eluting with dichloromethane. The fractions corresponding to the expected product are collected. These are combined and then concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 2.82 g of tert-butyl (1S) -1-benzyl-2-oxopropylcarbamate are obtained in the form of a white solid melting at 62 ° C. (1S) -1-Benzyl-2- [methoxy (methyl) amino] -2-oxoethylcarbamate Zez-2-butyl: As in Example 3 is carried out from 26.5 g of LN-Boc-phenylalanine 22 cm3 of N-methylmorpholine, 13 cm3 of isobutyl chloroformate, 10.14 g of Ν, Ο-dimethylhydroxylamine hydrochloride in 300 cm3 of dichloromethane. The product is treated in an identical manner and then purified by atmospheric pressure chromatography on a column of silica gel (63-200μ ganulometry, 6 cm diameter, 25 cm height) eluting with a mixture of dichloromethane-methanol (97/3). volumes). The fractions containing the expected product are collected. These are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 17.1 g of ZerZ-butyl (1S) -1-benzoyl-2- [methoxy (methyl) amino] -2-oxoethylcarbamate are obtained in the form of a colorless oil (R = 0.65 in a mixture). 97/3 dichloromethane-methanol, by volume, on Merck60F254r silica plate). 57 01 2286

Example 12

(-) - (4S) -4- (4-Ammobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride

The procedure is as in Example 9 starting from 0.59 g of (2S) -6 - {[(benzyloxy) carbonyl] amino} -2 - {[(tert-butylamino) carbothioyl] amino} hexanoateethyl in 6 g. cm3 of 6N hydrochloric acid. After concentration of the reaction macerated under the same conditions, the meringue obtained is taken up 3 times with diethyl ether which is decanted each time and the remaining insoluble by 10 cm3 of acetonitrile. The resulting crystallized product is drained, washed with acetonitrile and then dried under reduced pressure (5 kPa) at a temperature in the region of 20 ° C. 0.34 g of (-) - (4S) -4-dihydrochloride are obtained. - (4-Aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine, as cream-colored crystals melting at 170 ° C, (oto20 = -15.5 +/- 0.6 in 0.5% methanol). (2S) -6 - {[(Benzyloxy) carbonyl] amino) -2 - {[(tert-butylamino) carbothioyl] amino} ethyl exanoate: The procedure is as in Example 9 starting from 0.42 g of (5S) -5-

Benzyl amino-6-hydroxyhexylcarbamate and 0.24 cm of tert-butyl isothiocyanate in 30 cm3 of ethanol at a temperature in the region of 20 ° C. for 3 days. The reaction is terminated by additional addition of 0.48 cm 3 of isothiocyanate followed by heating for 1 hour at a temperature of about 80 ° C. After identical treatment, 0.6 g of ethyl (2S) -6 - {[(benzyloxy) carbonyl] amino} -2- {[(ieri-butylamino) caibothioyl] amino) hexanoate are obtained in the form of an oil. beige color with tendency to crystallization ,. (R = 0.62 in a mixture of 90/10 dichloromethane-methanol in volumes, on Merck silica plate 60F254R). Benzyl (5S) -5-Amino-6-hydroxyhexylcarbamate: A mixture of 4 g of benzyl (5S) -5 - {[(tert-butyloxy) carbonyl] amino} -6-hydroxyhexylcarbamate, 30 cm3 of trifluoroacetic acid and 20 cm3 of ethanol is stirred at a temperature of 20 ° C for 2 hours. After concentrating the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., the residue obtained is taken up in from 58 012286 ×. 50 cm of water, washed with 2 times 100 cm 3 of diethyl ether. The aqueous phase is decanted, alkalinized with sodium carbonate to pH 9-10, then extracted with 3 times 100 cm3 of dichloromethane. The combined extracts are washed with an aqueous solution of sodium chloride, then dried over magnesium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 2.0 g of benzyl (5S) -5-amino-6-hydroxyhexylcarbamate are obtained as a white solid which melts at 82 ° C. Benzyl (5S) -5 - {[(feri-Butyloxy) carbonyl] amino} -6-hydroxyhexylcaibamate: The procedure is as in Example 9 starting from 7 g of (2S) -6- / 10 {[(benzyloxy ) carbonyl] amino} -2 - {[(tert-butyloxy) carbonyl] amino} hexanoate demethyl in 70 cm3 of ethanol, 35 cm3 of tetrahydrofuran, 1 g of delithium chloride and 0.81 g of sodium borohydride. After 16 hours at a temperature of 20 ° C, the reaction mass is filtered, the cake washed with ethanol. The resulting leiltrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. After dissolving the residue obtained in 150 cm3 of dichloromethane, wash with 2 times 100 cm3 of an aqueous solution of sodium chloride and 2 times 100 cm3 of water, drying over magnesium sulfate, and finally concentration under the same conditions as above. 5.2 g of benzyl (5S) -5 - {[(ieri-butyloxy) carbonyl] amino} -6-hydroxyhexylcarbamate are obtained in the form of a white solid melting at 67 ° C. (2S) -6 - {[(Benzyloxy) carbonyl] amino} -2 - {[(tert-butyloxy) carbonyl] amino} hexanoate methyl: To a solution of 6.6 g of methyl ester hydrochloride; In 66 cm3 of methanol and 66 cm3 of tetrahydrofuran, cooled to a temperature of 0 ° C., 4.8 g of di-β-butyldicarbonate are added under an inert atmosphere and with stirring. then 5.7 cm3 of triethylamine and 10 cm3 of methanol. After stirring the mixture at a temperature of 5 ° C for 2 hours and then 2 hours at about 20 ° C; the reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in dichloromethane, the solution washed with 100 cm3 of water, dried over sodium sulfate.

Magnesium, filtered, concentrated under the same conditions as above. 7 g of methyl (2S) -6 - {[(benzyloxy) carbonyl] amino} -2 - {[(terZ-butyloxy) carbonyl] amino} hexanoate are obtained in the form of a cream-colored oil. (R = 0.90 Hans a mixture of dichloromethane-methanol 90/10 by volume, on a silica plate Merck 60F254r).

Example 13 (4S, 5R) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine

The procedure is as in Example 3, starting from 0.7 g of the diastereoisomer B of N- (tert-butyl) -N '- ((1S) -1-benzyl-2-hydroxypropyl) thiourea which is heated. at a temperature close to 100 ° C. for 5 hours in 8.3 cm 3 of 6N hydrochloric acid. After concentrating the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 50 ° C., 50 cm 3 of water are added to the residue obtained, and the solution is then extracted with dichloromethane (3 × 25 cm 3). The aqueous phase is made alkaline by addition of 0.5 cm3 of 30% sodium hydroxide solution, extracted with 3 times 50 cm3 of dichloromethane. The extracts are combined, dried over sodium sulphate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 50 ° C. An oil is obtained which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-63 μ, diameter 2 cm, height 28 cm), eluting with a mixture of dichloromethane-methanol. (95/5 empolumes). The fractions containing the expected product are collected. These are combined and then concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 0.10 g of (4S) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of a pale pink solid melting at 90 ° C. by becoming pasty (mixture of diastereoisomers: 82% cis [(4S, 5R) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine) 3-18% trans [(4S, 5S) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine)), (R = 0.15 in a mixture of dichloromethane-methanol 95/5 by volume, on Merck silica plate 60F254R). h

I 60 01228b

Example 14

(-) - (4R) -4-Butyl-4,5-dihydro-1,3-thiazol-2-ylamine oxalate

The procedure is as in Example 1 starting from 2.3 g of N- (tert-butyl) -N '- [(1R) -1-butyl-2-hydroxyethyl] thiourea in 32 cm 3 of aqueous hydrochloric acid. 6N. Afterconcentration under reduced pressure (5 kPa) at a temperature of 50 ° C, the residue obtained is taken up in 10 cm3 of water and then made alkaline by addition of 2 cm3 delusional 30% sodium hydroxide. After extraction with 3 times 50 cm3 of dichloromethane, the organic extracts are combined and then dried over sodium sulfate, concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 1.37 g of a yellow oil are obtained, the oxalate of which is made as follows: from 0.3 g of oil of

Above in 1 cm of acetone was added 0.24 g of oxalic acid dissolved in 1 cm of acetone. After precipitation of the salt, the medium is diluted with acetone (5 cc) and filtered. The crystals are washed with twice 4 cm3 of acetone and then dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 40.degree. C. 0.26 g of (-) - (4R) -4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine oxalate is obtained in the form of a white solid melting at 91 ° C .; (An20 = -7 under Na 589 nm and -70.1 +/- 1.2 lamp under Hg 365nm, in 0.5% methanol). N- (iron / -Butyl) -N '- [(1R) -1-butyl-2-hydroxyethyl] thiourea: The procedure is as in Example 2 starting from 1.14 g of (2R) -2-amino- 2-butyl-1-ethanol, 1.36 cm3 of Zer-butylisothiocyanate in 15 cm3 of ethanol, stirring 18 hours at a temperature of 20 ° C, then 3 hours at about 60 ° C. Afterconcentration of the reaction medium under reduced pressure (5 kPa) at a temperature of 40 ° C. 2.38 g of N- (tert-butyl) -N '- [(1R) -1-butyl-2-hydroxyethyl] thiourea are obtained in the form of a yellow oil (infra red spectrum (CH 2 Cl 2): 3620; 4430; 4410; 2960; 1560 1500; 1395; 1375 and 1205 cm -1). (2R) -2-Amino-hexanol: 3.7 g of L-methyl ester hydrochloride

Norleucine are solubilized in 20 cm3 of water. To this solution, the required amount of an aqueous solution of sodium carbonate is added with stirring at a temperature in the region of 20 ° C. to obtain a pH of 10. The medium is extracted with 3 times 50 cm3 of sodium acetate. 'ethyl. The extracts are combined, dried over sodium sulphate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 50 ° C.

2.95 g of methyl (2R) -2-amino-2-butyl acetate are obtained in the form of a yellow oil. Then proceed as in Example 2, from 2.9 g of methyl (2R) -2-amino-2-butyl-acetal, 1.14 g of sodium borohydride in 50 cm3 of ethanol. The reaction is carried out at a temperature in the region of -15 ° C., then the reaction mixture is stirred for 18 hours at a temperature in the region of 20 ° C. and finally at 30 ° C. for a temperature of about 80 ° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature in the region of 50 ° C., the residue obtained is purified by chromatography under argon pressure (50 KPa) on a silica gel column (particle size 40-63μ; diameter 2 cm, height 20 cm), eluting with a mixture of ethyl acetate-methanol (80/20 by volume). Fractions containing the expected product are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. 1.2 g of (2R) -2-amino-hexanol are obtained in the form of an oil having a tendency to crystallize; (An20 = + 2.6 +/- 0.4 in 0.5% ethanol).

Example 15

(+) - (5S) -5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride The procedure is as in Example 1 starting from 11.86 g of N - [( 2S) -2-hydroxypropyl] -N'-tert-butylthiourea in 168 cm 3 of 6N aqueous hydrochloric acid. After 3 hours of heating at a temperature of about 100 ° C. and an identical treatment, 2.30 g of hydrochloride of (+) - (5S) -5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine, as a white solid melting at 173 ° C (ao = + 73.8 +); - 1.4 in 0.5% methanol). N - [(2S) -2-Hydroxypropyl] -N'-tert-butylthiourea: The procedure is as in Example 1 starting from 5 g of (+) - (S) 4-amino-2-propanol, 8.43 g. g of ferric butyl isothiocyanate in 60 cm 3 of ethanol. After stirring the reaction medium for 5 hours at a

I

At a temperature of about 20 ° C., then concentration under reduced pressure (5 kPa) at a temperature of about 50 ° C., the white solid obtained is taken up with diethyl ether. The suspension is again concentrated under the same conditions as previously. 11.86 g of N - [(2S) -2-hydroxypropyl] -N'-tert-butylthiourea are obtained in the form of a white solid melting at 106 ° C.

Example 16 (-) - (4S) -4-Cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine

The procedure is as in Example 1 starting from 11.1 g of N- (tert-butyl) -N '- [(1S) -1-cyclohexylmethyl-2-hydroxyethyl] thiourea in 110 cm 3 of 6N hydrochloric acid. at a temperature of about 100 ° C for 2 hours. By identical treatment, 3.6 g of (-) - (4S) -4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in the form of a white solid melting at 169 ° C. C; (ccd20 = -33.9 +/- 0.8 in 0.5% methanol).

N- (Zeri-Butyl) -N '- [(1S) -1-cyclohexylmethyl-2-hydroxyethyl] thiourea: As in Example 3, 8.1 g of (+) - (2S) -2 were prepared -amino-3-cyclohexyl-1-propanol and 9.8 cm3 of iron / butyl isothiocyanate in 79 cm3 of ethanol. The reaction medium is stirred for 72 hours at a temperature of 20 ° C.After concentration under reduced pressure (5 kPa) at a temperature of 50 ° C <5 of the reaction mass, the oil obtained is taken up by 110 cm of petroleum ether. The crystals are filtered, dried under reduced pressure (10 Pa) at a temperature of about 60 ° C. 11.1 g of N- (tert-butyl) -N '- [(1S) -1-cyclohexylmethyl-2-hydroxyethyl] thiourea are obtained in the form of a white solid melting at 97 ° C.

Example 17

(+) - (4R) -4-Cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine Hydrochloride

The procedure is as in Example 1 starting from 2.9 g of N - (tert-butyl) -N '- [(1R) -1-cyclohexylmethyl-2-hydroxyethyl] thiourea in 28 cm 3 of aqueous hydrochloric acid. 6 0 by heating at a temperature of about 100 ° C for 2 h 15. By identical treatment, a solid is obtained which is purified by dissolution in 15 cm3 of water and extracted with 10 cm3 of dichloromethane. The aqueous phase is made alkaline by addition of 10 cm3 of 1N sodium hydroxide, extracted with twice 15 cm3 of ethyl acetate. The combined organic extracts are concentrated under reduced pressure (5 KPa) at a temperature of 40 ° C. The resulting paste is taken up twice with 20 cm3 of diethyl ether. The solid is filtered, dried in an oven under reduced pressure (10 Pa) at a temperature of 60 ° C. 0.4 g of (±) - (4R) -4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained as a white solid at 169 ° C .; (0¾20 = +31.8 +/- 0.9 in 0.5% ethanol). N-Butyl) -N '- [(1R) -1-cyclohexylmethyl-2-hydroxyethyl] thiourea: As in Example 3, 4.89 g of (2R) -2-amino-3 were prepared as in Example 3. cyclohexyl-1-propanol with 5.9 cm3 of i-butyl isothiocyanate in 48 cm3 of absolute ethanol. After stirring for 5 days at a temperature in the region of 20 ° C., the reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The solidobtained is taken up in 200 cm3 of petroleum ether, then the insoluble matter is filtered off and dried in air. 2.96 g of N- (tert-butyl) -N '- [(1R) -1-cyclohexylmethyl-2-hydroxyethylthiourea are obtained in the form of a white solid (R = 0.29 in the acetate mixture). ethyl-cyclohexane, on Merck silica plate 60F254R). (2R) -2-Amino-3-cyclohexyl-1-propanol: The procedure is as in Example 1 starting from 6.2 g of (2R) -2-amino-3-cyclohexylpropionate ethyl and 1.93 g sodium hydrobromide in 120 cm3 of absolute ethanol at about 5 ° C for 10 minutes. The medium is brought to room temperature, stirred again for 3h30minutes. After further cooling to about 5 ° C. and a new addition of 40.94 g of borohydride, followed by stirring at a temperature in the region of 20 ° C. for 65 hours, the reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40.degree. ° C. A solid is obtained which is purified by chromatography under argon pressure (100 kPa), on a column of silica gel (particle size 40-63 μ, 320 g), eluting with pure methanol. The fractions containing the expected product are collected. These are combined and then concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 5.16 g of (2R) -2-amino-3-cyclohexyl-1-propanol are obtained in the form of a tacky white solid (R = 0.25 in methanol on a Merck silica plate 60F254R). (2R) -2-Amino-3-cyclohexylpropionate ethyl: The procedure is as in Example 2 from 10 g of P-cyclohexyl- (D) -alanine hydrochloride in 96 cm3 of ethanol absolute passed through a current dry hydrochloric acid at a temperature of about 0 ° C for 20 minutes. After heating at about 80 ° C. for 4 days and then cooling to 0 ° C., a stream of hydrochloric acid is refluxed for 20 minutes followed by heating at a temperature in the region of 80 ° C. for 20 hours. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C., while the residue obtained is solubilized in 200 cm 3 of water, made alkaline by the addition of 19 g of solid potassium carbonate. After evaporation, the resulting solid is taken up in 200 cm3 of ethanol at a temperature of 80 ° C. The insoluble matter is filtered and the filtrate is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in 130 cm3 of ethanol at room temperature. The insoluble material is filtered while the new filtrate is evaporated under the same conditions as above. 4.8 g of ethyl (2R) -2-amino-3-cyclohexylpropionate are obtained in the form of a whitish paste (R = 0.80 in the ethanol-ammonia mixture, 90/10 by volume, based on Merck60F254r silica plate).

Example 18 4- (3-Nitrophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine

The procedure is as in Example 2 starting from 1.49 g of N- (/ er / -butyl) -N '- [2-hydroxy-1- (3-nitrophenyl) ethyl] thiourea in 14 cm3 of acid. 6N aqueous hydrochloric acid by heating at a temperature in the region of 100 ° C. for 2.5 hours. By identical treatment, 1.01 g of 4- (3-nitrophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine is obtained in the form of a cream-colored solid, m.p. 232. ° C.

Example 19

(+) - (4R) -4- (4-Pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride

Under the conditions of Example 1, 0.46 g of N- (tert-butyl) -N '- [(1R) -2-hydroxy-1- (4-pyridylmethyl) ethyl] thiourea are obtained, which The mixture is heated in 5 cm3 of 5N aqueous hydrochloric acid for 16 hours at a temperature in the region of 100 ° C. After concentration of the reaction mass under reduced pressure (5 kPa) at a temperature of 40 ° C, an oil is obtained which is taken up in 3 cm3 of 2-propanol. The resulting crystalline precipitate is filtered off, washed with 2-propanol and dried in air. 0.1 g of (+) - (4R) -4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of an orange solid, m.p. 150 ° C (20 °, + 38.3 +/- 0.9 in 0.5% MeOH). N- (tert-Butyl) -N '- [(1R) -2-hydroxy-1- (4-pyridylmethyl) ethyl] thiourea: A solution of 0.1 g of (1R) -1- (4-pyridylmethyl) - 2-hydroxyethylcarbamate of iert-butyl in 3 cm3 of 4N hydrochloric dioxane is stirred for 16 hours at a temperature of 20 ° C. The reaction mass is concentrated under reduced pressure (5 kPa) at a temperature of 40 ° C. 0.075 g of a white product is obtained which is dissolved in 4 cm 3 of ethanol. After the addition of 0.08 cm 3 of triethylamine and 0.09 cm 3 of tert-butyl isothiocyanate, the mixture is stirred for 16 hours at a temperature in the region of 20 ° C. and then for 6 hours at a temperature in the region of 50 ° C. The mixture is evaporated under reduced pressure (5 kPa) at a temperature of 40 ° C, and the residue obtained is triturated in 20 cm3 of water. The water is decanted, the oil is added with ethanol, and then concentrated under the conditions of the above.

0.10 g of N- (1-yl-butyl) -N '- [(1R) -2-hydroxy-1- (4-pyridylmethyl) ethyl] thiourea are obtained in the form of an orange-colored oil (R = 0.50 66 012286 in ethyl acetate-acetic acid-water, 4/1/1 by volume, on Merck desilice plate 6OF254 *). (1 R) -1- (4-Pyridylmethyl) -2-hydroxyethylcarbamate tert-butyl: To a mixture of 1 g of Boc-D-4-pyridylalanine in 10 cm3 of tetrahydrofuran, we add inert atmosphere 0.52 cm3 of triethylamine then the mixture is cooled to a temperature of about -18 ° C. After addition of 0.47 cm 3 of chloroform-isobutyl, stirring is continued for 30 minutes at a temperature between -18 and -10 ° C. The mixture is rapidly filtered and 0.28 g of sodium hydrobromide dissolved in 2 cm 3 of water are then added to the filtrate. The mixture is stirred for 1 hour at a temperature in the region of 0 ° C. and then for 16 hours at a temperature in the region of 20 ° C. The mixture is made alkaline by adding an aqueous solution of potassium carbonate and then stirred in the presence of ethyl acetate. Organic phase is decanted then washed with water, dried over magnesium sulphate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. The residue obtained is purified by chromatography under a pressure of argon of 50 kPasur a column of silica gel (40-63μ particle size, diameter 2.2 cm, 30 cm high) eluting first with ethyl acetate alone, and collecting 30 cm3 fractions. Fractions 1 to 18 are separated and then eluted with a mixture of ethyl acetate-methanol (90/10 by volume). Fractions 23 to 26 are collected and combined. After concentration under reduced pressure (5 kPa) at a temperature of 40 ° C., 0.10 g of tert-butyl (1 R) -1- (4-pyridylmethyl) -2-hydroxyethylcarbamate are obtained in the form of oil [Infrared spectrum (CH2Cl2): 3618; 3434; 2981; 1708 1501; 1367; 1168 and 1057 cm -1).

Example 20

(+) - (4R, 5R) -5-methyl- (4R, 5R) -4- (pyridin-4-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride

A suspension of 1.96 g of N-tert-butyl- [7 '] - [(1 R) 2RS) -1- (pyridin-4-yl-methyl) -2-hydroxypropyl] -thiourea in 25 cm 3 of 5N hydrochloric acid is heated to a temperature of about 100 ° C for 18 hours. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue obtained is purified by chromatography on a CHIRALCEL OD 20μ column in a heptane-isopropanol-triethylamine mixture (90/10 / 0.1 by volume). Fractions containing the expected product are concentrated under reduced pressure (1 kPa) at a temperature of about 40 ° C. The residue obtained is purified by atmospheric pressure chromatography on a column of silica gel (particle size 40-60 μm, diameter 1.2 cm, height 30 cm), eluting with a mixture of ethyl acetate-acetic acid-water ( 2/1/1 in volumes). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue obtained is taken up in 5 cm 3 of 5 N hydrochloric acid and ethanol puisconcentré under reduced pressure (2 kPa) at a temperature of 40 ° C. After drying in the desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C., 0.4 g of (+) (4R, 5R) -4- (pyridin-4-yl-methyl) -5 dihydrochloride are obtained. methyl-4,5-dihydro-thiazol-2-ylamine in the form of a very hygroscopic meringue [NMR spectrum] H (300 MHz, (CD3) 2SO d6, δ in ppm): 1.44 (d, J = 7 Hz: 3H), 3.22 (dd, J = 13.5 and 7.5 Hz: 1H) ; 3.32 (dd, J = 13.5 and 5 Hz: 1H); 3.90 (mt: 1H); 4.37 (mt: 1H); 8.01 (broad d, J = 6 Hz: 2H); 8.88 (bd, 6 Hz: 2H); 9.34 (slarge: 1H); 9.85 (brs: 1H); 10.31 (mf: 1H); (aD20 = +75.3 +/- 1.3 in 0.5% ethanol). (1R, 2RS) -1- (pyridin-4-ylmethyl) -2-hydroxypropyl] thiourea: A solution of 1.41 g of (3R, 2RS); ) -3-amino-4- (pyridin-4-yl) -butan-2-ol in 30 cm3 of ethanol, with addition of 1.08 cm3 of Fe / Y-butylisothiocyanate and then 2.16 cm3 of Td-ethylamine is heated for 16 hours. with stirring at a temperature of 50 ° C. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature of 40 ° C, taken up in 10 cm3 of water and washed with 2 times 30 cm3 of dichloromethane, dried over sulfate of magnesium, filtered, evaporated under the conditions of the above and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature of 40 ° C. 2 g of β-tert-butyl-β- [(1 R, 2 S) -1- (pyridin-4-yl-methyl) -2-hydroxy-propyl] -thiourea are obtained in the form of an oil. orange [Spectrum of 68 012286 NMR. h (300 MHz, (CD3) 2SO d6, δ in ppm). We observe the mixture of two diastereoisomers A and B in the respective proportions 70/30, δ = 0.99 (d, J = 6.5 Hz: 0.9H); 1.09 (d, J = 6.5 Hz: 2.1H); 1.37 (s: 6.3H); 1.41 (s: 2.7H); 2.74 (dd, J-14.5 and 9 Hz: 0.7H); from 2.75 to 2.90 (mt: 0.6H); 2.93 (dd, J = 14.5 and 5 Hz: 0.7H), 3.55 to 3.80 (mt: 1H); from 4.35 to 4.60 (mf: 1H); 4.65 (mf: 0.3H); 4.88 (mp: 0.7H); from 7.10 to 7.25 (mt: 1H); 7.17 (brs: 0.7H); 7.26 (broad d, J = 6 Hz: 1.4H); 7.31 (broad d, J = 6 Hz: 0.6H); 7.44 (brs: 0.3H); from 8.35 to 8.50 (mt: 2H).

(3H, 2RS) -3-amino-4- (pyridin-4-yl) -butan-2-ol dihydrochloride: To a solution of 1.85 g of N - [(1R, 2RS) -1- (pyridine) 4-tert-butyl 4-yl-methyl-2-hydroxy-propyl] -carbamate in 20 cm3 of dioxane is added with stirring, at a temperature of 20 ° G, a solution of 20 cm3 of 4N hydrochloric acid in dioxane . The mixture is stirred at a temperature in the region of 20 ° C. for 5 hours, and then it is concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 1.8 g (3R, 2RS) -3-amino-4- (pyridin-4-yl) -butan-2-ol dihydrochloride is obtained in the form of a yellow solid (M.M.N. ^ H (300 MHz, (CDs ^ SO d6 with addition of some drops of CD3COOD d4, δ in ppm) We observe the mixture of two diastereoisomers A and B in the respective proportions 70/30, δ = 1.18 and 1.20 (2d, J = 6.5 Hz: 3H in all), 3.13 (dd, J = 10.5 and 6 Hz: 0.7H), 3.20 to 3.35 (mt: 1.3H) from 3.45 to 3.65 (mt: 0.6 H), 3.72 (mt: 0.7H), 3.96 (mt: 0.7H), from 8.05 to 8.15 (mt: 2H) 8.88 (d, J = 6Hz: 2H) N - [(1R, 2RS) -1- (Pyridin-4-ylmethyl) -2-hydroxypropyl] -carbamate tert-butyl: To a solution of 2 g of N - [(1R) -1- (pyridin-4-ylmethyl) -2-oxo-propyl] butylcarbamate in 20 cm3 of ethanol, with stirring and at room temperature. temperature close to 10 ° C. 0.43 g of sodium borohydride is added, followed by stirring at a temperature in the region of 20 ° C. for 18 hours The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. , taken up in 50 cm3 of water, extracted with 100 cm3 of ethyl acetate, dried over sulfat e magnesium, filtered and concentrated under reduced pressure (1 kPa), at a temperature of 40 ° C. 1.83 g of N-69 01 2286 [(1 R, 2RS) -1- (pyridin-4-yl-methyl) -2-hydroxy-propyl] -carboxylcarbamate are obtained in the form of a yellow solid. [NMR spectrum. (300 MHz, (CD3) 2SO d6, δ in ppm). We observe the mixture of two diastereoisomers A and B in the proportions 70/30; δ = 1.03 (d, J = 6.5 Hz: 0.9H); 1.09 (d, J = 6.5 Hz: 2.1H); 1.28 (s: 2.7H); 1.30 (s: 6.3H); from 2.45 to 2.55 (mt: 0.7H); 2.61 (dd, J = 13.5 and 10.5 Hz: 0.3H); 2.81 (dd, J = 13.5 and 4 Hz: 0.3H); 3.01 (dd, J = 13.5 and 2 Hz: 0.7H); from 3.40 to 3.70 (mt: 2H); 4.70 (d, J = 5.5 Hz: 0.3H); 4.78 (d, J = 5.5 Hz: 0.7H); 6.53 (d, J-9 Hz: 0.3H); 6.67 (d, J = 9 Hz: 0.7H); 7.20 (broad d, J = 6 Hz: 1.4H); 7.25 (broad d, J = 6 Hz: 0.6H); from 8.40 to 8.50 (mt: 2H) j. Tertiary butyl N - [(lR) -1- (pyrid-4-ylmethyl) -2-oxo-propyl] carbamate: A mixture, under an inert atmosphere, of 5.3 g of N- {2- [ N-Methoxy-N- (methyl) amino] -2-oxo- (1 R) -1- (pyridin-4-ylmethyl) -ethyl} -carbamate of tert-butyl in 120 cm3 of tetrahydrofuran is cooled to a temperature of temperature close to 0 ° C. 17 cm 3 of a solution of 3 M methyl magnesium bromide in diethyl ether are then added over 1 hour, followed by stirring for 1 hour at 0 ° C. and 18 hours at a temperature in the region of 20 ° C. The reaction medium is cooled again to a temperature in the region of -0 ° C., then 30 cm3 of 1N hydrochloric acid and 100 cm3 of water are added dropwise, the mixture is extracted with ethyl acetate and the mixture is washed with water. 100 cm3 of water. The combined organic phases are dried over sodium sulphate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue obtained is purified by chromatography at atmospheric pressure on a column of silica gel (particle size 60-200 μm, diameter 4 cm, height 35 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 0.2 g of N - [(lR, 2RS) -1- (pyridin-4-yl-methyl) -2-oxo-propyl] -carbamyl carbamate [RM.N. 1H (300 MHz, (CD3) 2SO d6, δ in ppm): 1.34 (s: 9H); 2.16 (s: 3H); 2.71 (dd, J = 14 and 10.5 Hz: 1H); 3.08 (dd, J = 14 and 4.5 Hz: 1H); 4.21 (mt: 1H), 7.27 (broad d, J = 5.5 Hz: 2H); 7.34 (d, J = 8 Hz: 1H); 8.47 (broad d, J = 5.5 Hz: 2H)]. N-{[N-Methoxy-N- (methyl) amino] -2-oxo (1 R) -1- (pyrid-4-ylmethyl) -ethyl} -carbamate of tert-butyl: A solution, under an inert atmosphere, of 20 g of DN-Boc-pyridylalanine and 16.5 cm 3 of N-methylmorpholine in 500 cm 3 of dichloromethane is cooled to a temperature in the region of -15 ° C. Isobutyl chloroformate (9.75 cc) is then run in and the mixture is stirred for 15 minutes at this temperature. After addition of 7.61 g of Ν, Ο-dimethylhydroxylamine hydrochloride, stirring is continued for 1 hour at a temperature in the region of -15 ° C then 18 hours at room temperature. The reaction medium is supplemented with 250 cm3 of water puisextrait per 100 cm3 of dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure (2 kPa) at a similar temperature.

Z of 50 ° C. The residue is purified on a column of silica gel (particle size 60-200 μm, height 35 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 6.5 g of N- {2- [N-methoxy-N- (methyl) amino] -2-oxo- (1R) -1- (pyridin-4-yl-methyl) -ethyl} -carbamate are obtained. teri-butylesous form of a thick yellow oil [NMR spectrum (300 MHz, (CD3) 2SOd6, δ in ppm): 1.33 (s: 9H); 2.78 (dd, J = 13.5 and 10 Hz: 1H); 2.89 (dd, J = 13.5 and 4.5 Hz: 1H); 3.14 (brs: 3H); 3.76 (s wide: 3H); 4.63 (mt: 1H); 7.24 (mt: 1H); 7.27 (broad d, J = 5.5 Hz: 2H); 8.4S (d wide, J = 5.5 Hz: 2H)].

Examples 21 and 22

(+) - 4- (Thiazol-5-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride and (-) - 4- (Thiazol-5-ylmethyl) -4,5-dihydrochloride dihydro-thiazol-2-ylamine

A racemic mixture of 0.38 g of (4RS) -4- (thiazol-5-ylmethyl) -4,5-dihydro-thiazol-2-ylam dihydrochloride is separated on a CHIRALCEL ODIOp column in a heptane-isopropanol mixture. -2-triethylamine (80/20/20 by volume). The fractions containing the expected product are concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. to give 0.053 g of (+) - 4- (thiazol-5-ylmethyl) -4,5-dihydro-dihydrochloride. thiazol-2-ylamine and 0.057 g of (- ????????? (thiazol-5-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride.

(±) - 4- (Thiazol-5-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride: R.M.N. 1H (300 MHz, (CD3) 2SO d6, δ in ppm): from 3.20 to 3.40 (mt: 3H); 3.70 (dd, J = 11.5 and 8 Hz: 1H); 4.58 (mt: 1H); 7.85 (s: 1H); 9.10 (s: 1H); 9.26 (mp: 1H); 9.67 (mf: 1H); 10.13 (s wide: 1H).

(-) - 4- (Thiazol-5-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride: NMR spectral. h (300 MHz, (CD3) 2SO d6, δ in ppm): from 3.20 to 3.40 (mt: 3H); 3.70 (dd, J -12 and 8 Hz: 1H); 4.58 (mt: 1H); 7.85 (s: 1H); 9.10 (s: 1H); 9.26 (mf: 1H); 9.67 (mf: 1H); 10.14 (brs: 1H); (αη20 = -4.2 +/- 0.6 in 0.5% methanol)

(4RS) -4- (Thiazol-5-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride: A solution of 0.56 g of N- (tert-butyl) -N '- [( 1RS-1-hydroxymethyl-2- (thiazol-5-yl) -ethyl] -thiourea in 5.5 cm 3 of 6N hydrochloric acid is heated to a temperature of about 110 ° C for 3 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 60 ° C., taken up in 4 cm3 of ethanol and 6 cm3 of diethyl ether and evaporated under the same conditions as above. The residue is taken up in 6 cm3 of ethanol, filtered and the solid is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. and then dissolved in a solution of 5.5 cm 3 of 6N hydrochloric acid and brought at reflux at a temperature of 110 ° C for 9 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. to obtain 0.54 g of dihydrochloride. of (4RS) -4- (thiazol-5-ylmethyl) -4,5-dihydro-thiazol-2-ylamine as a pasty solid [NMR spectrum] H (300 MHz, (CD3) 2SO d6, δ in ppm): from 3.20 to 3.40 (mt: 3H); from 3.60 to 3.80 (mt: 1H); 4.57 (mt: 1H); 7.85 (s: 1H); 9.10 (s: 1H); 9.26 (mf: 1H); 9.66 (mf: 1H); 10.13 (bs: 1H) N - (1H-butyl) -N '- [(1RS) -1-hydroxymethyl-2- (thiazol-5-yl) -ethyl] -thiourea: A solution of 0 56 g of (2RS) -2-amino-3- (thiazol-5-yl) propan-1-ol hydrochloride in 8 cm 3 of ethanol are added 0.52 cm 3 of triethylamine and then 0.55 cm 3 The mixture is stirred at a temperature in the region of 20 ° C. for 18 hours and then heated at a temperature in the region of 60 ° C. for 1 hour 30. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa), at 50.degree. a temperature close to 40 ° C, taken up in 6 cm3 of water and washed with 3 times 20 cm3 of dichloromethane, dried over magnesium sulfate, filtered, evaporated under the conditions of above and then dried in a desiccator under reduced pressure (0 1 kPa) at a temperature in the region of 40 ° C. 0.56 g of N '- (ier-butyl) -N - [(1RS) -1-hydroxymethyl-2- (thiazol-5-yl) - are obtained. ethyl] -thiourea as a yellow viscous oil [Spectrum of R 1H NMR (300 MHz, (CD3) 2SO d6, δ in ppm): 1.43 (s: 9H); 3.03 (dd, J = 15 and 7 Hz: 1H); 3.19 (dd, J = 15 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 2H); 4.41 (mt: 1H); 4.97 (t, J = 5 Hz: 1H); 7.23 (d, J = 8 Hz: 1H); 7.30 (slarge: 1H); 7.67 (s: 1H); 8.94 (s: 1H)].

(2RS) -2-amino-3- (thiazol-5-yl) propan-1-ol hydrochloride: A solution of 0.63 g of N - [(1RS) -1-hydroxymethyl-2- (thiazol) -5-yl) -ethyl] -acetamide in 7.86 cm3 of 6N hydrochloric acid is heated to a temperature of 110 ° C for 3 hours. The reaction mixture is filtered, concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C., taken up in isopropyl ether, concentrated in the above conditions, taken up in 10 cm3 of isopropyl ether, filtered and dried at room temperature. desiccator under reduced pressure (0.1 kPa) at a temperature of 40 ° C. 0.56 g of (2RS) -2-amino-3- (thiazol-5-yl) propan-1-ol hydrochloride are obtained in the form of a beige solid melting at 192 ° C. (NMR Spectrum). H (300 MHz, (CD3) 2SO d6, δ in ppm): 3.21 (d, J = 7 Hz: 2H); 3.35 (mt: 1H); 3.48 (dd, J = 11.5 and 5.5 Hz: 1H); 3.61 (dd, J = 11.5 and 4 Hz: 1H); 7.83 (brs: 1H); 8.19 (mf: 3H); 9.10 (bs: 1H) N - [(1RS) -1-Hydroxymethyl-2- (thiazol-5-yl) ethyl] acetamide: To a solution of 1.2 g of (2RS) 12 Ethyl acetylamino-3- (thiazol-5-yl) -propanoate in 20 cm3 of ethanol is added with 0.4 g of sodium borohydride and then, under an inert atmosphere, the mixture is stirred at a temperature in the region of 20 ° C. After 18 hours, 0.1 g of sodium borohydride are added again and the mixture is stirred for 24 hours at a temperature in the region of 20 ° C. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature of 40.degree. C. The residue is taken up in 10 cm 3 of water and extracted with 3 times 30 cm 3 of ethyl acetate The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. Lerésidu is chromatographed under an argon pressure of 60 kPa, on a silica-degel column (particle size 40-63μ, diameter 3.5 cm, height 31 cm), eluting for 100 cm. 3 dichloromethane, 600 cm3 of a mixture of dichloromethane-methanol (98/2 by volume), 500 cm3 of a mixture of dichloromethane-methanol (96/4 enn. volumes) and 1 dm3 of a mixture of dichloromethane-methanol (90/10 by volume).

The fractions containing the expected product are combined and then concentrated in the above conditions. 0.63 g of N - [(1RS) -1-hydroxymethyl-2- (thiazol-5-yl) -ethyl] -acetamide are obtained in the form of a yellow oil (NMR Spectrum). (300 MHz, (CD3) 2SO d6, δ in ppm): 1.80 (s: 3H); 2.85 (dd, J = 15 and 9 Hz: 1H); 3.16 (dd, J = 15 and 5 Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.87 (mt: 1H); 4.85 (mt: 1H); 7.65 (s: 1H); 7.79 (d, J = 8.5 Hz: 1H); 8.91 (s: 1H)]. (2RS) -2-ethyl acetylamino-3- (thiazol-5-yl) propanoate: To a solution of 3.3 g of diethyl 2-acetylamino-2- (thiazol-5-ylmethyl) -malonate in 70 cm3 of ethanols are added dropwise 2.7 cm3 of 6N sodium hydroxide. The mixture is stirred for 5 hours and then 1.5 cc of 12N hydrochloric acid are added dropwise; a precipitate is forming. It is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. to give a brown solid which is dried for 12 hours at a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40.degree. This residue is taken up with 50 cm3 of dioxane and then heated at a temperature of 100 ° C for 3 hours 30. The reaction medium is evaporated under reduced pressure (1 kPa) at a temperature of 40 ° C. The residue is chromatographed under an argon pressure of 60 kPa, on a column of silica gel (particle size 40-63 μ, diameter 3.5 cm, height 31 cm), eluting with 675 cm 3 of dichloromethane, 500 cm 3 of a dichloromethane-methanol mixture (99/1 by volume), 500 cm3 of a mixture of dichloromethane-methanol (98/02 by volume), 500 cm3 of a mixture of dichloromethane-methanol (97/3 by volume), 500 cm3 of a mixture of dichloromethane-methanol (95/5 by volume), 500 cm3 of a mixture of dichloromethane-methanol-ammonia (12 / 1.5 / 0.5 by volume) and 500 cm3 of a mixture of dichloromethane-methanol-ammonia (12/3 / 0.5 by volume). The fractions containing the expected product are combined and then concentrated in the above conditions. 0.8 g of ethyl (2RS) -2-acetylamino-3- (thiazol-5-yl) -propanoate are obtained in the form of a brown oil (mass spectrum: DCI m / z = 243MH4). Diethyl acetylamino-2- (thiazol-5-ylmethyl) -malonate: After dissolving A <1.24 g of sodium in 20 cm 3 of ethanol, 10.86 cm of diethyl acetamido-malonate are added and then heated to a temperature of about 75 ° C. After 15 minutes, a solution of 5-chloromethyl-thiazole in 20 cm 3 of ethanol is added, followed by heating for 2 hours at a temperature in the region of 75 ° C. The reaction unit is evaporated under reduced pressure (1 kPa), at a temperature of 40 ° C. The residue is chromatographed under an argon pressure of 60 kPa, on a column of silica gel (particle size 60-200μ, diameter 6.5 cm, height 40 cm), eluting with a mixture of dichloromethane-methanol (99/1). in volumes), a mixture of dichloromethane-methanol (98/02 by volume) then a mixture of dichloromethane-methanol (95/5 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 3.3 g of diethyl 2-acetylamino-2- (thiazol-5-ylmethyl) -malonate are obtained in the form of a solid orange [NMR Spectrum]. H (300 MHz, (CD3) 2SO d6, δ in ppm): 1.18 (t, J = 7.5 Hz: 6H); 2.00 (s: 3H); 3.75 (s: 2H); 4.17 (q, J = 7.5 Hz: 4H); 7.61 (s: 1H); 8.37 (brs: 1H); 9.00 (s: 1H)]. 5-Chloromethyl-thiazole: To a solution of 8.2 g of 5-methyl-thiazole in 250 cm3 of carbon tetrachloride, 11 g of N-chlorosuccinimide and then 0.1 g of benzoyl peroxide are added. The mixture is heated for 20 hours at a temperature of about 80 ° C and then exposed to U.V. for 5 hours. The reaction mixture is h

The mixture is cooled, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 20 ° C. 6.4 g of 5-chloromethyl-thiazole are obtained [Mass spectrum: DCIm / z = 134MH +]

Example 23

(+) - (4R) -4- (pyrazin-2-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride

A racemic mixture of 2.9 g of (4RS) -4- (pyrazin-2-yl-methyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride is separated on a CHIRALCEL ODIOp column in a heptane-ethanol-triethylamine mixture. (80/20 / 0.1 · in volumes). Fractions containing the expected product are concentrated under reduced pressure (1 kPa) at a temperature of about 40 ° C. The residue obtained is dissolved in 5 cm3 of ethanol and then 6 cm3 of hydrochloric acid in solution in diethyl ether and 15 cm3 of diethyl ether are added. After filtration, washing with 15 cm3 of diethyl ether and drying gave 0.371 g of (+) - (4R) -4- (pyrazin-2-yl-methyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride. in the form of a beige solid melting at 154 ° C. [NMR spectrum H (300 MHz, (CD3) 2SO d6, δ in ppm): 3.22 (d, J = 6.5 Hz: 2H); 3.45 (dd, J = 11.5 and 5.5 Hz: 1H); 3.75 (dd, J = 11.5 and 8 Hz: 1H); 4.73 (mt: 1H); 8.60 (broad d, J = 2.5 Hz: 1H); 8.63 (dd, J = 2.5 and 1.5 Hz: 1H); 8.66 (brs: 1H); 9.09 (mp: 1H); 9.58 (mf: 1H); 9.95 (brs: 1H); (an20 = +46.3 +/- 1.1 in 0.5% methanol)].

(4RS) -4- (pyrazin-2-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride: A solution of 7.2 g of N- (ie; 7-butyl) -N'- [(1RS) -1-hydroxymethyl-2- (pyrazin-2-yl) ethyl] -thiourea in 20 cm3 of 5N hydrochloric acid is heated to a temperature of 110 ° C for 20 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 55 ° C. and then taken up in ethanol while concentrating under the same conditions as above. The residue is chromatographed under atmospheric pressure, on a column of silica gel (particle size 40-60μ, diameter 4 cm, height 30 cm), eluting with a mixture of acetic acid-water-ethyl acetate (1/1/4 in volumes). The fractions containing the expected product are combined and then concentrated under the above conditions. The oil obtained is taken up in ethanol and the precipitate obtained is filtered off and dried under reduced pressure (0.1 KPa) at a temperature in the region of 40 ° C. to obtain 2.9 g of (4R, S) dihydrochloride. 4 - (pyrazin-2-ylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine as a brown solid, mp 190 ° C. (NMR spectrum. 1η (300 MHz, (CDa) ₂SO d6, δ in ppm): 3.23 (d, J = 6 Hz: 2H); 3.43 (dd, J = 11.5 and 5.5 Hz: 1H); 3.72 (dd, J = 11.5 and 7.5 Hz: 1H); 4.74 (mt: 1H); 8.59 (brs: 1H); 8.64 (brs: 1H); 8.67 (brs: 1H); 9.29 (mf: 1H); 9.77 (mf: 1H); 10.16 (s wide: 1H) J. N - (tert-Butyl) -N '- [(1RS) -1-hydroxymethyl-2- (pyrazin-2-yl-ethyl) -thiourea: To a solution of 7.91 g of (2RS) dihydrochloride 2-Amino-3- (pyrazin-2-yl) -propan-1-yl in 80 cm 3 of ethanol is added with stirring 11.2 cm 3 of triethylamine then 7.2 cm 3 of feri-butyl-isothiocyanate The mixture is heated at a temperature of about 50 ° C. for 18 hours After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C., taken up in 100 cm3 of water and extracted with dichloromethane. The organic phases are combined, washed with 50 cm 3 of water, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. 7.2 g of N- (ieri-butyl) are obtained. ) -N '- [(1RS) -1-hydroxymethyl-2- (pyrazin-2-yl) -ethyl] -thiourea as a colorless paste [Mass spectrum: DCI m / z = 269 MH + -] 20 (2RS) -2-amino-3- (pyrazin-2-yl) -propan-1-ol dihydrochloride A solution of 11 g of N - [(1RS) -1-hydroxy-methyl-2- (pyrazin-2-yl) -ethyl] -acetamide in 30 cm3 of 5N hydrochloric acid is heated at a temperature in the region of 115 ° C 18 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. 7.9 g of (2RS) -2-amino-3 (pyrazin-2-yl) propan-1-ol dihydrochloride are obtained in the form of a black paste. [Mass spectrum: DCIM / z = 154MH + ] N - [(1RS) -1-Hydroxymethyl-2- (pyrazin-2-yl) -ethyl] -acetamide: To a solution of 8.5 g (2RS) -2-acetylamino-3- (pyrazin-2-yl) ) -ethylpropanoate in 100 cm3 of ethanol

2.8 g of sodium borohydride are added and the mixture is then stirred at a temperature in the region of 20 ° C. After 18 hours the reaction medium is taken up in 50 cm3 of water and 100

0 cm of dichloromethane and the aqueous phase is concentrated under reduced pressure (1 kPa) at a temperature of 40 ° G. 11 g of N - [(1RS) -1-hydroxymethyl-2- (pyrazin-2-yl) -ethyl] -acetamide are obtained in the form of a brown paste [NMR Spectrum]. * H (300 MHz, (>> 3) 2SO d6 with addition of a few drops ofCDjCOOD d4, δ enppm): 1.71 (s: 3H); 2.81 (dd, J = 14.5 and 9 Hz: 1H); 3.03 (dd, J = 14.5 and 5Hz: 1H); 3.35 (dd, J = 11 and 6 Hz: 1H); 3.42 (dd, J = 11 and 5Hz: 1H); 4.11 (mt: 1H); 7.75 (residual d, J = 8.5 Hz: 0.5H); 8.45 (d, J = 2.5 Hz: 1H); 8.50 (brs: H); 8.53 (mt: 1HJ). (2RS) -2-ethyl acetylamino-3- (pyrazin-2-yl) -propanoate: To a solution of 14 g of diethyl 2-acetylamino-2- (pyrazin-2-ylmethyl) -malonate in 240 g. cm 3 of ethanol is added dropwise 12 cm3 of 6N sodium hydroxide and then stirred at a temperature of 20 ° C. After 1 hour the reaction medium is neutralized with 6 cm3 of 12N hydrochloric acid. After stirring for 2 hours at a temperature of 20 ° C., the reaction medium is filtered and the filtrates are concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. The residue is taken up in 200 cm 3 of dioxane, refluxed for 2 hours and concentrated as above. 8.5 g of ethyl (2RS) -2-acetylamino-3- (pyrazin-2-yl) -propanoate are obtained. in the form of a cream solid [NMR spectrum (300 MHz, (CDjHSO d6, δ enppm): 1.13 (t, J = 7 Hz: 3H), 1.80 (s: 3H), 3.12 (dd, J = 14 and 8.5 Hz: 1H), 3.22 (dd, J = 14 and 6 Hz: 1H), 4.07 (q, J = 7 Hz: 2H), 4.71 (mt: 1H), 8.36 (d, J = 8 Hz: 1H), 8.52 (d, J = 2.5 Hz: 1H), 8.55 to 8.65 (mt: 2H),

Diethyl 2-acetylamino-2- (pyrazin-2-ylmethyl) -malonate can be prepared according to C.Petermann and J. L. Fauchere; Helv.Chim.Acta (1983), 66 (5), 1513-1518.

Examples 24 and 4- (Imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2-ylamine, enantiomer Aet4-

(Imidazol-1-yl-methyl) -4,5-dihydro-thiazol-2-ylamine, enantiomer B 1 78 012286

A racemic mixture of 0.75 g of (4RS) -4- (imidazol-1-yl-methyl) -4,5-dihydro-thiazol-2-ylamine is separated on a column CHERALCEL ODIOp in a mixture heptane-isopropanol-2 triethylamine (80/20/20 by volume). The fractions containing the expected product are combined and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. to obtain 0.215 g of 4- (imidazol-1-yl-methyl) -4,5-dihydro-thiazole. 2-ylamine, enantiomer A and 0.21 g of 4- (imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2-ylamine, enantiomer B-4- (hnidazol-1-ylmethyl) - 4,5-dihydro-thiazol-2-ylamine, enantiomer A: NMR spectrum 1H (300 MHz, (CD3) 2SO d6, δ enppm): 2.93 (dd, J = 1 and 7 Hz: 1H); 3.25 (dd, J = 11 and 7 Hz: 1H); 4.03 (d, J = 6 Hz: 2H); 4.38 (mt: 1Η0Γ, 6.49 (mf: 2H), 6.88 (brs: 1H), 7.20 (brs: 1H), 7.64 (brs: 1H). 1-Imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2-ylamine, Enantiomer B: 1H NMR Spectrum (300 MHz, (CD3) 2SO d6, δ in ppm): 2.96 (dd, J = 11 and 7.5 Hz: 1H), 3.20 to 3.40 (mt: 1H), 4.05 (d, J = 6 Hz: 2H), 4.41 (mt: 1H), 6.88 ( s: 1H); 7.20 (brs: 1H); 7.64 (brs: 1H). (4RS) -4- (Imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2 -ylainine: To a solution of 1.39 g of N-[(4RS) -4- (imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2-yl] -carbamate in 5 cc 5 ml of 4N hydrochloric acid are added to the dioxane and then methanol is added to dissolve the reaction medium.After stirring at a temperature in the region of 20 ° C. for 48 hours, the reaction medium is concentrated under reduced pressure (1 kPa). ), at a temperature in the region of 40 ° C., washed with isopropyl ether, with ethyl acetate and then with methacrylate. The suspension obtained is filtered and the filtrate is evaporated as above and then chromatographed on a column of silica gel, eluting with a 28% mixture of dichloromethane-methanol-ammonia (50-5-1 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions to obtain 0.33 g of (4RS) -4- (imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2-ylamine in the form of yellowish oil [NMR spectrum] H (300 MHz, (CD3) 2 SO d6, δ in ppm): 2.93 012286 (mt: 1H); 3.26 (mt: 1H); 4.03 (d, J = 6 Hz: 2H); 4.39 (mt: 1H); 6.49 (mp: 2H), 6.87 (mt: 1H); 7.20 (mt: 1H); 7.63 (brs: 1H)]. Tert-Butyl N - [(4RS) -4- (imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2-yl] carbamate: To a solution of 0.085 g of sodium hydride in 20 cm3 dimetylformamide added 0.21 g of imidazole dissolved beforehand in 10 cm3 of dimethylformamide. After the disappearance of the sodium hydride, a solution of 1 g of N- [(4RS) -4- (p-toluenesulfonyloxy-methyl) -4,5-dihydro-thiazol-2-yl] carbamate is added. Butylated in 10 cm3 of dimethylformamide and then stirred at a temperature of 70 ° C for 3 hours. The reaction medium is diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure (1 KPa) at a temperature in the region of 40 ° C. The residue obtained is chromatographed on an alumina column, eluting with ethyl acetate and a mixture of ethyl acetate-methanol (80/20 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions to obtain 0.25 g of N - [(4RS) -4- (imidazol-1-ylmethyl) -4,5-dihydro-thiazol-2-yl] β-butyl carbamate as a yellow sticky mass [Mass spectrum: DCIM / z = 283 ^111 / = = 183 (M-C5H7O2) 4]. N- [(4RS) -4- (p-Toluenesulfonyloxy-methyl) -4,5-dihydro-thiazol-2-yl] -carbamate-t-butyl: A solution of 0.8 g of N - [(4RS) 4-hydroxymethyl-4,5-dihydro-thiazol-2-yl] -carbamate, 0.76 g of p-toluenesulfonyl chloride and 0.56 cm3 of triethylamine in 25 cm3 of dichloromethane is stirred for 16 hours at a temperature of 20 ° C. The solution obtained is concentrated under reduced pressure (1 kPa) at a temperature of 40 ° C. The evaporation residue obtained is purified by chromatography under atmospheric pressure on a desilicose gel column (particle size 60-200μ, diameter 2 cm, height 25 cm), eluting with a mixture of cyclohexane-ethyl acetate (70/30 by volume). ) and collecting fractions of 30 cm3. The fractions containing the expected product are pooled under the conditions of the above. 0.8 g of N-[(4RS) -4 - (p-toluenesulfonyloxy-methyl) -4,5-dihydro-thiazol-2-yl] carbamate of ZerZ-butyl are obtained in the form of a white solid. [NMR spectrum (300 MHz, CDCl3, δ in ppm): 1.48 (s: 9H); 2.46 (s: 3H); 3.10 (dd, J = 11.5 and 5.5 Hz: 1H); 3.33 (dd, J-11.5, and 8.5 Hz: 1H); 3.97 (dd, J = 9.5 and 8 Hz: 1H); 4.06 (dd, J = 9.5 and 4.5 Hz: 1H); 4.43 (mt: 1H); 7.36 (d, J = 8 Hz: 2H); 7.80 (d, J = 8 Hz: 2H); from 8.50 to 9.40 (mf inhalated: 1H)]. N-[(4RS) -4-Hydroxymethyl-4,5-dihydro-thiazol-2-yl] -carbamate-4-butyl ester: A solution of 2 g of 2 - [(ier-butoxycarbonyl) imino] - (4RS) - 4 - [(ter-butoxycarbonyl) oxy] -methyl-1,3-thiazolidine-3-carboxylic acid-4-butyl ester in 20 ml of metbanol is added 10 cm of aqueous sodium hydroxide N and then stirred at a similar temperature at 20 ° C for 4 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50.degree. The residue obtained is taken up with 30 cm3 of water, filtered, washed with ethyl acetate and then with water. 0.37 g of tert-butyl N- [(4RS) -4-hydroxymethyl-4,5-dihydro-thiazol-2-yl] carbamate are obtained in the form of a white solid. [Mass spectrum: DCI m / z = 233 MH4 m / z = 177 (M-C4H7) 4]. 2 - [(tert-Butoxycarbonyl) imino] - (4RS) -4 - [(tert-butoxycarbonyl) imino] - (4RS) -4 - [(tert-butoxycarbonyl) imino] -methyl-1,3-thiazolidine-3-carboxylic acid carboxylate: To a solution of 1, 98 g of (4RS) -4-hydroxymethyl-4,5-dihydro-thiazol-2-ylamine in 20 cm3 of dichloromethane are added 10.91 g of di-zer-butyldicarbonate and 2.81 cc of triethylamine and then stirred with temperature around 20 ° C. After 4 hours, 3 cm 3 of triethylamine are again added, followed by stirring for 16 hours at a temperature in the region of 20 ° C. 50 cm3 of water are added to the reaction mixture and decanted. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. 7 g of tert-butyl 2 - [(tert-butoxycarbonyl) imino] - (4RS) -4 - [(tert-butoxycarbonyl) oxy] methyl-1,3-thiazolidine-3-carboxylate are obtained in the form of a white solid [Mass spectrum: DCI m / z = 433 MH 4 m / z = 333 (M-C 5 H 7 O 2) +].

(4RS) -4-Hydroxymethyl-4,5-dihydro-thiazol-2-ylamine: A solution of 90 g of 1-β-butyl-3- (2-hydroxy-1-hydroxymethyl-ethyl) - thiourea in 500 cm3 of 6N hydrochloric acid is stirred at a temperature in the region of 100 ° C. After 3 hours, the reaction mixture is cooled to a temperature in the region of 20 ° C. and is then concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 ° C. The residue obtained is taken with 100 cm3 of water, basified with 100 cm3 of 5N sodium hydroxide and then concentrated as previously. The oil obtained is stirred for 20 hours at a temperature of 20 ° C in 300 cm3 of ethanol, filtered, washed with 5 times 50 cm3 of ethanol and 3 times 100 cm3 of methanol. The various filtrates are combined, evaporated under reduced pressure (1 kPa), at a temperature of 40 ° C and then crystallized in 400 cm3 of ethanol to obtain 31 g of (4RS) -4-hydroxymethyl-4,5-dihydro-thiazol 2-ylamine · as a white solid melting at 122 ° C [Infra-red spectrum (KBr): 3311; 3164; 1648 1601; 1349; 1051 and 982 cm -1). 1-Fez-Butyl-3- (2-hydroxy-1-hydroxymethyl-ethyl) -thiourea: To a solution of 14.6 g of 2-amino-1,3-propanediol in 245 cm3 of ethanol is added 30, 4 cm3 of tert-butyl isothiocyanate and then stirred at a temperature of 20 ° C for 94 hours. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 ° C. and the residue is triturated in a mixture of 160 cm 3 of petroleum ether and 26 cm 3 of ethanol, filtered and then dried under reduced pressure (FIG. 0.1 kPa) at a temperature in the region of 60 ° C. 30 g of 1-e-y-butyl-3- (2-hydroxy-1-hydroxymethyl-ethyl) -thiourea are obtained in the form of a solid white [NMR spectrum. (250 MHz, (CD3) 2SO d6, δ in ppm): 1.42 (s: 9H); 3.38 (mt: 2H); 3.54 (mt: 2H); 4.17 (mf: 1H); 4.70 (t, J = 5 Hz: 2H); 7.08 (d, J = 8Hz: 1H); 7.38 (s: 1H)).

Example 26

(+) - (4R) -4- (Thiazol-4-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride

A solution of 1.75 g of N- (tert-butyl) -N '- [(1R) -1-hydroxymethyl-2- (thiazol-4-yl) ethyl] -thiourea in 20 cm3 of hydrochloric acid 6N is heated to a temperature of about 110 ° C. for 20 hours The reaction medium is concentrated under reduced pressure (1 KPa), at a temperature in the region of 60 ° C., taken up in 5 cm3 of ethanol and then concentrated in Same conditions as above The residue is taken up with 5 cm 3 of ethanol, then filtered and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. 0.54 g of dihydrochloride are obtained. (+) - (4R) -4- (thiazol-4-ylmethyl) -4,5-dihydro-thiazol-2-ylamine as a 195 ° C melting solid [TH-NMR spectrum (300 MHz (CD3) 2SO d6, δ in ppm): 3.67 (mt: 2H), 3.41 (dd, J = 11.5 and 5.5 Hz: 1H), 3.68 (dd, J = 11); , 5 and 8 Hz: 1H), 4.63 (mt: 1H), 7.59 (d, J = 2 Hz: 1H), 9.14 (d, J - 2 Hz: 1H), mf: 1H); 9.66 (mf: 1H); 10.04 (brs: 1H); ao20 = +24.2 +/- 0.8 in 0.5% methanol)]. N- (tert-Butyl) -N '- [(1R) -1-hydroxymethyl-2- (thiazol-4-yl) ethyl] thiourea: A solution of 2.5 g of N - [(1R) 1-hydroxymethyl-2- (thiazol-4-yl) -ethyl) -carbamate deferf-butyl in 20 cm3 of 6N hydrochloric acid and 20 cm3 of dioxane is stirred at a temperature of 20 ° C for 18 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. Oh, 1.9 g of white solid. The solid obtained is taken up in 6 cm3 of absolute ethanol, to which 2 cm3 of triethylamine and then 2.1 cm3 of ieri-butylisothiocyanate are added. Lemange is stirred at a temperature of 50 ° C for 20 hours. The reaction unit is concentrated under reduced pressure (1 kPa) at a temperature of 40 ° C. The residue is taken up in water and the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated under the above conditions. The residue is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature of 40 ° C. 1.75 g of N - (/ er-butyl) -N '- [(1R) -1-hydroxymethyl-2- (thiazol-4-yl) -ethyl] -thiourea are obtained in the form of a yellow solid [Spectrum NMR (300 MHz, (δb / SO d6, δ in ppm): 1.41 (s: 9H), 2.96 (dd, J = 15 and 7 Hz: 1H), 3.05 (dd, J = 15 and 7 Hz: 1H), 3.41 (mt: 2H), 4.62 (mf: 1H), 4.85 (t, J = 5 Hz: 1H), 7.21 (d, J = 8.5 Hz); : 1H), 7.23 (slarge: 1H), 7.37 (d, J = 2 Hz: 1H), 9.04 (d, J = 2 Hz: 1H).) 83 01 2286 N - [(1R) ) 1-Hydroxymethyl-2- (thiazol-4-yl) -ethyl] -carbamate-4-butyl: A solution of 3 g of BOC-D- (4-thiazolyl) alanine in 50 cm3 of tetrahydrofuran is added with stirring 1 The reaction medium is cooled to a temperature in the region of -18 ° C., and isobutyl chloroformate is then added with stirring and under an atmosphere of ether, after stirring for 40 minutes at a temperature in the region of -15.degree. C. the reaction medium is filtered rapidly in the cold and the filtrate is added to the filtrates, at a temperature in the region of -15 ° C. and with stirring, a solution of 0.85 g of sodium borohydride dissolved beforehand in 6 cm 3 of water. After 18 hours of agitafion at a temperature of 20 ° C the reaction medium is diluted with 100 cm3 of water and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 ° C. 2.5 g of N - [(1R) -1-hydroxymethyl-2- (thiazol-4-yl) -ethyl] -carbamate of 4-butyl are obtained in the form of a colorless oil (infra-red spectrum (CCI4)). 3442, 3368, 2980, 2932, 2874, 1710, 1501, 1392, 1367, 1243, 1171, 1048 and 875 cm -1).

Example 27

(+) - (4R) -4- (3-Aminopropyl) -4,5-dihydro-thiazol-2-yl amine dihydrochloride

A solution of 9.6 g of benzyl N - [(4R) -4- (3-e-butyl-thioureido) -5-hydroxy-pentyl] carbamate in 50 cm3 of 6N hydrochloric acid is heated to a temperature of around 110 ° C for 18 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C., repressuccessively with 30 cm 3 of ethanol and 20 cm 3 of isopropanol, concentrating under the same conditions as above between each wash. The solid obtained is taken up in ethanol and diethyl ether, filtered and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. to obtain 2.8 g of (+) dihydrochloride. - (4R) -4- (3-aminopropyl) -4,5-dihydro-thiazol-2-ylamine as a white solid melting at 166 ° C [NMR spectrum] H (300 MHz, (CD 4 SO 4 d 6, δ in ppm): 1.55 to 1.85 (mt: 4H), 2.81 (mt: 2H), 3.25 (dd, J = 11 and 6 Hz: 1H), 3.69 (dd, J = 84 01 2286 11 and 8 Hz: 1H), 4.27 (mt: 1H), 8.16 (mf: 3H), 9.50 (mw spread: 2H), 9.50 to 10.60 (mf very spread: 1H), (ap2 + 7.5 +/- 0.4 in 0.5% methanol) N - [(4R) -4 Benzyl (3-iert-Butyl-thioureido) -5-hydroxy-pentyl] -carbamate: A solution of 16 g of (2R) -5 - {[(benzyloxy) carbonyl] amino) -2- (3-) ethyl pentanoate in 200 cm 3 of ethanol and 100 cm 3 of tetrahydrofuran are added with stirring to 2.24 g of lithium chloride, and after stirring for 15 minutes at a temperature in the region of 0.degree. 24 g of sodium borohydride After stirring for 20 hours at a temperature in the region of 20 ° C., 0.5 g of sodium borohydride are added again, the reaction mixture is filtered and the filtrates are concentrated under reduced pressure (1 kPa). ), at a temperature of 40 ° C. The residue is cbromatographed under atmospheric pressure, on a desilice gel column (60-200μ particle size; diameter 5.6 cm; height 40 cm), eluting with a mixture of dichloromethane-ethyl acetate (8/2 by volume) and a mixture of dichloromethane-ethyl acetate (6/4 by volume). Fractions containing the expected product are combined and concentrated under the conditions above. 9.6 g of benzyl N - [(4R) -4- (3-tert-butyl-thioureido) -5-hydroxy-pentyl] -carbamate are obtained in the form of a yellow oil (M.M.N. (300 MHz, (CD3) 2SO d6, δppm): δ1, 30-1.60 (mt: 4H); 1.42 (s: 9H); 3.00 (mt: 2H); 3.25 to 3.40 (mt: 1H), 3.45 (mt: 1H); 4.21 (mf: 1H); 4.76 (mf: 1H); 5.02 (s: 2H); 7.09 (d, J = 8.5 Hz: 1H); 7.17 (brs: 1H); 7.27 (t, J = 5.5 Hz: 1H); from 7.30 to 7.45 (mt: 5H)]. (2R) -5- {[(Benzyloxy) carbonyl] amino} -2- (3-tert-butyl-thioureido) -pentanoate ethyl: To a solution of 13 g of (2R) -2-amino hydrochloride In 7.5 ml of tert-butyl isothiocyanate in ethyl acetate (200 ml) of ethanol is added thereto and the mixture is stirred at a temperature in the region of 20.degree. After 48 hours, the reaction medium is concentrated under reduced pressure (1 kPa), at a temperature of 40 ° C to obtain 16 g of (2R) -5 - {[(benzyloxy) carbonyl] amino} -2- Ethyl (3-tert-butyl-thioureido) pentanoate as a colorless oil [Mass spectrum: m / z = 409 M * - m / z = 232 (C13H14NO3) + m / z = 142 ( 232-PhCH) + m / z = 91 (C7H7) +]. 012286 85

(2R) -2-amino-5 - [(benzyloxy) caibonyl] amino-pentanoic acid hydrochloride: A solution of 12.5 g of (2R) -2-amino-5 - [(() - ( benzyloxy) carbonyl] amino-pentanoic acid in 200 cm3 of ethanol is cooled to a temperature in the region of -20 ° C. 6.5 cm3 of thionyl chloride are then added dropwise and the mixture is stirred at a temperature in the region of 20 ° C. for 18 hours. The reaction unit is concentrated under reduced pressure (1 KPa), at a temperature of 40 ° C to obtain 13 g of (2R) -2-amino-5 - [(ben2yloxy) carhonyl] amino-pentanoate hydrochloride of ethyl [Spectrum mass: DCI m / z = 295MH *]. ~

(2R) -2-amino-5 - [(benzyloxy) carbonyl] amino-pentanoic acid hydrochloride: To a solution of 15.5 g of D-omithine hydrochloride in 1 dm3 of water is added 30 g of The mixture is heated to a temperature in the region of 100 ° C for 2 hours, filtered hot and washed with water. The filtrates are cooled to a temperature of 20 ° C. and, with stirring, 14.5 g of magnesium oxide are added. The reaction medium is cooled to a temperature in the region of 0 ° C., while 15.5 cm 3 of benzyl chloroformate is run in 4 times. After 18 hours at a temperature of 20 ° C, the mixture is filtered. The solid is washed successively with 3 times 30 cm3 of water and 3 times 30 cm3 of diethyl ether and then suspended in 500 cm3 of N hydrochloric acid with a slight stream of hydrogen sulfide for 2 hours. The suspension is filtered and the solid washed with 0.5N hydrochloric acid. The filtrates are brought to pH 4-5 with dilute ammonia, formation of a white precipitate, After filtration and drying in the desiccator, 12.5 g of (2R) -2-amino-5-hydrochloride are obtained. [(benzyloxy) carbonyl] amino-pentanoic acid as a white solid [NMR spectrum] (300 MHz, 25 (CD3) 2SO d6, 8 ppm): from 1.40 to 1.80 (mt: 4H); 2.99 (mt: 2H); 3.11 (mt: 1H); 5.02 (bs: 2H); from 7.25 to 7.45 (mt: 6H).

I 86 01 2286

Example 28

(+) - (4R) -4- (4-hydroxy-benzyl) -4,5-dihydro-thiazol-2-ylamine hydrochloride

A solution of 0.2 g of N- (ieri-butyl) -N '- [(1R) -1-hydroxymethyl-2- (4-hydroxyphenyl) -ethyl] -thiourea in 2.6 cc of acid 6N hydrochloric acid is heated at a temperature in the region of 110 ° C. for 18 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 55 ° C. and then successively with 10 cm 3 of isopropyl ether, 10 cm 3 of diethyl ether, 10 cm 3 of pentane, 10 cm 3 of petroleum ether, 10 cm 3 of isopropyl ether by concentrating under the same conditions as above between each wash. The solid obtained is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. to obtain 0.098 g of (+) - (4R) -4- (4-hydroxy-benzyl) hydrochloride. 5-dihydro-thiazol-2-ylamine as an orange solid [NMR spectrum] H (300MHz, (CD3) 2SO d6, δ in ppm): 2.78 (dd, J = 13.5 and 7.5 Hz: 1H); 2.88 (dd, J = 13.5 and 5.5 Hz: 1H); 3.26 (dd, J = 11.5 and 6 Hz: 1H); 3.55 (dd, J = 11.5 and 7.5 Hz: 1H); 4.45 (mt: 1H); 6.74 (d, J = 8.5 Hz: 2H); 7.07 (d, J = 8.5 Hz: 2H); 9.09 (mf: 1H); 9.41 (s: 1H); 9.56 (mf: 1H); 9.97 (ss: 1H), (an20 = +9.5 +/- 0.5 in 0.5% ethanol)]. N- (ieri-Butyl) -N '- [(1R) -1-hydroxymethyl-2- (4-hydroxy-phenyl) -ethyl] -thiourea: A to a solution of 0.2 g of 4 - [(2R 2-amino-3-hydroxy-propyl] -phenol in 10 cm3 of absolute ethanol is added 0.15 cm3 of triethylamine then 0.18 cm3 of tert-butylisothiocyanate. The mixture is stirred at a temperature in the region of 20 ° C. for 18 hours and then heated at a temperature in the region of 60 ° C. for 4 hours. Aftercooling, the reaction mixture is evaporated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. and then chromatographed under an argon pressure of 60 kPa, on a silica gel column (40-63μ particle size, 2.5 diameter). cm, height 29 cm), eluting with a mixture of dichloromethane-methanol (98/2 by volume). The fractions containing the expected product are combined and then concentrated under the conditions of the above. 0.2 g of N- (tert-butyl) -N '- [(1R) -1-yl) hydroxymethyl-2,4-hydroxyphenyl) ethyl] thiourea are obtained in the form of a colorless viscous oil [NMR spectrum (300 MHz, (CD3) 2SO d6, δ in ppm): 1.42 (s: 9H); 2.63 (dd, J 13.5 and 8 Hz: 1H); 2.72 (dd, J = 13.5 and 5.5 Hz: 1H); from 3.25 to 3.40 (mt: 2H); 4.29 (mf: 1H); 4.83 (t, J = 4.5 Hz: 1H); 6.67 (d, J = 8 Hz: 2H), 7.05 (d, J = 8 Hz: 2H); 7.15 (d, J = 8 Hz: 1H); 7.26 (brs: 1H); 9.16 (s: 1H-4 - [(2R) -2-Amino-3-hydroxypropyl)] phenol: To a solution of 20.5 cc of 4N hydrochloric acid in dioxane is added under stirring and inert atmosphere, at a temperature in the region of 20 ° C., a solution of 2.2 g of tert-butyl N- [(1R) -1-hydroxymethyl-2- (4-hydroxy-phenyl) ethyl] carbamate in 24 cm 3 dichloromethane and 4 cm3 of dioxane. The mixture is heated to a temperature of about 60 ° C for 18 hours, then cooled and concentrated under reduced pressure (1 kPa) at a temperature of about 60 ° C. The residue is taken up in 50 cm3 of dichloromethane, filtered, triturated in 20 cm3 of diethyl ether, refiltered, washed with 2 times 5 cm3 of diethyl ether and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40.degree. ° C. 1.4 g of 4 - [(2R) -2-amino-3-hydroxy-propyl] -phenol are obtained in the form of a beige-colored solid melting at 156 ° C. [NMR Spectrum]. (300 MHz, (CD3) 2SO d6, δ in ppm): 2.69 (dd, J = 13 and 9Hz: 1H); 2.79 (dd, J = 13 and 5.5 Hz: 1H); 3.23 (mt: 1H); from 3.30 to 3.45 (mt: 1H), 3.51 (ddd, J = 11.5-5 and 4.5 Hz: 1H); 5.32 (t, J = 5 Hz: 1H); 6.73 (d, J = 8.5 Hz: 2H); 7.06 (d, J = 8.5 Hz: 2H); 7.95 (mf: 3H); 9.37 (s: 1H)). Tertiary butyl N - [(lR) -1-hydroxymethyl-2- (4-hydroxy-phenyl) -ethyl] -carbamate: A solution of 4.38 g of methyl BOC-D-tyrosynate in 25 cm 3 of tetrahydrofuran with stirring and under an inert atmosphere, at a temperature of 20 ° C., a solution of 29.6 cm3 of 1M aluminum lithium hydride in tetrahydrofuran is added. After adding 60 cm3 of tetrahydrofuran the reaction mixture is heated to a temperature of 70 ° C for 3 hours. The reaction mixture is cooled and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 60 ° C. The evaporation residue is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. and then chromatographed under an argon pressure of 60 kPa, on a column of silica gel (particle size 40.degree. 63μ, diameter 7 cm, height 24 cm), eluting with 10 dm3 of a mixture of dichloromethane-methanol (98/2 by volume), 2 dm3 of a mixture of dichloromethane-methanol (95/5 by volume) and 2 dm3 a mixture of dichloromethane-methanol (90/10 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 2.2 g of tert-butyl N- [(lR) -1-hydroxymethyl-2- (4-hydroxyphenyl) ethyl] carbamate are obtained in the form of a white meringue (NMR Spectrum). (400 MHz, (CT> 3) 2SO d6, δ in ppm): 1.35 (s: 9H), -2.46 (dd, J = 14 and 8 Hz: 1H); 2.68 (dd, J = 14 and 6 Hz: 1H); from 3.15 to 3.40 (mt: 2H> j 3.50 (mt: 1H), 4.61 (mt: 1H), 6.48 (d, J = 8.5 Hz: 1H); 65 (d, J = 8 Hz: 2H), 6.97 (d, J = 8 Hz: 2H), 9.11 (brs: 1H).

Example 29 (+) - 4- (Pyridin-4-ylsulfanylmethyl) -4,5-dihydro-thiazol-2-ylamine

A racemic mixture of (4RS) -4- (pyridin-4-ylsulfanylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride (1.75 g) was separated on a 10μ CHCHRALCEL OD column in a isopropanol-2-triethylamine (80/20 / 0.1 in volumes) to obtain 0.43 g of (+) - 4- (pyridin-4-ylsulfanylmethyl) -4,5-dihydro-thiazol-2-ylamine [Spectrum NMR H (300 MHz, (δbhSO d6, δ enppm): 3.12 (dd, J = 11 and 6.5 Hz: 1H), 3.20 (d, J = 6.5 Hz: 2H); 44 (dd, J = 11 and 7.5 Hz: 1H), 4.32 (mt: 1H), 6.49 (mf: 2H), 7.30 (dd, J = 5 and 1.5 Hz: 2H); 8.37 (dd, J = 5 and 1.5 Hz: 2H), (aD20- +13.3 +/- 0.6 in 0.5% methanol)].

(4RS) -4- (Pyridin-4-ylsulfanylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride: To a solution of 0.356 g of N - [(4RS) -4- (pyridin-4-ylsulfanylethyl) ) 4-tert.-4,5-dihydro-thiazol-2-yl] -carbamate in 5 cm 3 of methanol and 20 cm 3 of dioxane is added 5 cm 3 of 4N hydrochloric acid in dioxane and then stirred at a temperature of 20 ° C for 18 hours. The reaction medium is concentrated under reduced pressure (5 kPa), at a temperature in the region of 40 ° C., taken up in diisopropyl ether and then filtered to obtain 0.287 g of dihydrochloride (89%) (4RS) -4- (pyridin-4- ylsulfanylmethyl) -4,5-dihydro-thiazol-2-ylamine as cream solids [NMR spectrum] * Η (300 MHz, (CD ^ O d6, δ in ppm): 3.45 (dd, J "11 and 4.5 Hz: 1H), 3.61 (dd, J = 14 and 7 Hz: 1H) 3.69 (dd, J = 14 and 5.5 Hz: 1H), 3.80 (dd, J = 12 and 8 Hz: 1H), 4.59 (mt: 1H), 8.00 (d. , J = 6.5 Hz: 2H), 8.66 (broad d, J = 6.5 Hz: 2H), 9.60 (mf: 1H), 9.81 (mf: 1H), from 10.00 to 10.50 (mfetal: 1H) tert-Butyl N- [(4RS) -4- (pyridin-4-ylsulfanylmethyl) -4,5-dihydro-thiazol-2-yl-3-carbanylate: A suspension of 1.5 g of teri-butyl N- [(4RS) -4- (p-toluenyloxysmethyl) -4,5-dihydro-thiazol-2-yl] carbamate in 50 cm3 of acetonitrile until dissolved then 0.604 g of 4-mercaptopyridine are added with stirring.When 1.07 g of potassium decarbonate are cooled to a temperature in the region of 20 ° C., the mixture is stirred for 48 hours at a temperature in the region of 20 ° C. The filtrate is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 ° C. The residue obtained is taken up again. in ethyl acetate and water and decanted. The organic phase is washed with a sodium chloride solution, dried over magnesium sulphate and chromatographed on an alumina column, eluting with successive mixtures of ethyl acetate-cyclohexane (50/50 by volume). The fractions containing the expected product are purified by chromatography on a column of silica gel, eluting with ethyl acetate. The fractions containing the expected product are combined and then concentrated in the conditions of above. 0.356 g of N-[(4RS) -4- (pyridin-4-ylsulfanylmethyl) -4,5-dihydro-thiazol-2-yl] -carbamate are obtained in the form of a yellow oil. NMR (300 MHz, (CD3) 2SO d6, δ in ppm): 1.42 (s: 9H); 3.09 (dd, J = 11.5 and 6 Hz: 1H); 3.29 (mt: 2H); 3.40 (dd, J = 11.5 and 8Hz: 1H); 4.25 (mt: 1H); 7.35 (dd, J = 5 and 1.5 Hz: 2H); 8.40 (dd, J = 5 and 1.5 Hz: 2H); from 9.70 to 10.00 (mf spread: 1H) 90 012286

Example 30

(4R) -4- (1-Oxy-pyridin-4-ylmethyl) -4,5-dihydro-thiazol-2-ylamine hydrochloride

A solution of 0.6 g of N- (/ er / -butyl) -N '- [(1R) -1-hydroxymethyl-2- (1-oxy-pyridin-4-yl) -ethyl] -thiourea in 6 g. cm3 of 6N hydrochloric acid is heated to a temperature of 110 ° C for 18 hours. The reaction medium is concentrated under reduced pressure (1 kPa), at a temperature in the region of 55 ° C., taken up twice with 20 cm 3 of ethanol, concentrated under the same conditions as above, taken up in 10 cm of ethanol, filtered and dried. to the desiccator under reduced pressure (0.1 kPa) at a temperature of 40 ° C to obtain 0.296 g of (4R) -4- (1-oxy-pyridin-4-ylmethyl) -4,5-dihydro hydrochloride Thiazol-2-ylamine in the form of cream crystals [NMR spectrum] (300 MHz, (CT ^ SO d6, δ in ppm): 3.04 (AB limit: 2H); 3.34 (dd, J = 12 and 5.5 Hz: 1H); 3.68 (dd, J); = 12 and 8 Hz: 1H), 4.63 (mt: 1H), 7.75 (d, J = 7 Hz: 2H), 8.65 (d, J = 7Hz: 2H), 9.30 (mf : 1H); 9.79 (mf: 1H); 10.30 (slarge: 1H). N- (butyl) -N '- [(1R) -1-hydroxymethyl-2- (1-oxy-pyridin) 4-yl) ethyl] -thiourea: A solution of 1.5 g of (2R) -2-amino-3- (1-oxy-pyridin-4-yl) -propan-1-ol hydrochloride in 30 g. cm 3 of absolute ethanol is added 2.6 cm 3 of triethylamine then 1.53 cm 3 of teri-butylisothiocyanate.When 20 cm3 of methanol have been added, the mixture is stirred at a temperature in the region of 20 ° C. for 18 hours and then is concentrated under reduced pressure (1 kPa), at a temperature in the region of 40 ° C. To the evaporation residue, 1 cm 3 of triethylamine and then 1.5 cm 3 of tert-butyl isothiocyanate are added to the residue of evaporation, and the mixture is stirred at a temperature in the region of 20 ° C. for 48 hours The reaction medium is concentrated under reduced ssion (5 kPa), at a temperature of 40 ° C, taken up in 25 cm3 of ethyl acetate, filtered, washed with 10 cm3 of ethyl acetate and 20 cm3 of isopropyl ether. The triethylamine hydrochloride is removed by passage over an alumina column. 0.6 g of N- (tert -Butyl) -N '- [(1R) -1-hydroxymethyl-2- (1-oxy-pyridin-4-yl) -ethyl] -thiourea are obtained in the form of white crystals [ Rf = 0.36 in a dichloromethane-methanol mixture (90/10 by volume) on a Merck 60 F254 alumina plate (E type).

(2R) -2-Amino-3- (1-oxy-pyridin-4-yl) -propan-1-ol hydrochloride: A solution of 2 g of N - [(1R) -1-hydroxymethyl-2- tert-butyl-oxy-pyridin-4-yl) -ethyl] -carbamate in 20 cm3 of dioxane is added with stirring, at a temperature of 20 ° C, a solution of 20 cm3 of 4N hydrochloric acid in the dioxane. The mixture is stirred at a temperature of 20 ° C for 18 hours, then it is taken up in 40 cm of dioxane, stirred for 30 minutes and filtered. The precipitate is washed with 10 cm3 of dioxane and then with 25 cm3 of isopropyl ether and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 ° C. 1.54 g of (2R) -2-amino-3- (1-oxy-pyridin-4-yl) -propan-1-ol hydrochloride are obtained in the form of a pale yellow solid (NM-NMR spectrum). . (300 MHz, (CD & SO d6, δ in ppm): 3.08 (d, J = 6 Hz: 2H), from 3.40 to 3.55 (mt: 2H), from 3.55 to 3, 70 (mt: 1H), 7.78 (d, J = 6.5 Hz: 2H), 8.26 (bs: 3H), 8.71 (d, J = 6.5 Hz: 2H).

Tertiary butyl N - [(1 R) -1-Hydroxymethyl-2- (1-oxy-pyridin-4-yl) -ethyl] carbamate: To a solution of 1.01 g of m-chloroacetic acid. 77% perbenzoic acid in 10 cm3 of dichloromethane is added 1 g of (lR) -1- (pyridin-4-yl-methyl) -2-hydroxyethylcarbamate of butyl-butyl in 5 cm3 of dichloromethane and then heated to a temperature of 60 ° C. After 45 minutes, 0.65 g of m-chloro-perbenzoic acid is added again and then heated for 1 hour at a temperature in the region of 60 ° C., and then the above operation is repeated. After heating for 2 hours at a temperature close to 60 ° C., the mixture is cooled and then the reaction medium is taken up in 50 cm 3 of dichloromethane and 50 cm 3 of N sodium hydroxide. The aqueous phase is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. C., taken up in 50 cm 3 of dichloromethane, dried over magnesium sulphate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. 0.15 g of N- [(1R) -1-hydroxymethyl-2- (1-oxy-pyridin-4-yl) -ethyl-carbamate, Zer-butyl, are obtained (NMR Spectrum). H (300 MHz, (CD3) 2SO d6, δ in ppm): 1.32 (s: 9H); from 2.45 to 2.60 (mt: 1H); 2.86 (very broad d, J = 13.5 Hz: 1H); from 3.20 to 3.45 (mt: 2H); 3.63 (mt: 1H); 4.80 (mt: 1H); 6.67 (broad d, J - 9 Hz: 1H); 7.23 (broad d, J = 5.5 Hz: 2H); 8.14 (broad, J = 5.5 Hz: 2H)].

Example 31

(+) - 4- (1,2,4-Triazol-1-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride A racemic mixture of 0.35 g of (4RS) dihydrochloride 4- (1,2,4) -triazol-1-ylmethyl-4,5-dihydro-thiazol-2-ylamine is separated on a CHIRALPAK AS20μ column in a heptane-ethanol-triethylamine mixture (80/20/0, 1 in volumes). The fractions containing the expected product are combined and then concentrated under pressure

Z reduced (1 kPa), at a temperature of 40 ° C to obtain 0.08 g of (+) - 4- 10 (1,2,4-triazol-1-yl-methyl) -4,5-dihydro Thiazol-2-ylamine as a yellow solid [NMR spectrum] H (300 MHz, (Ceb 2 SO d6, d in ppm): 3.46 (dd, J = 11.5 and 4.5 Hz: 1H), 3.76 (dd, J = 11.5 and 8, 5 Hz: 1H), 4.51 (d, J = 5 Hz: 2H), 4.69 (mt: 1H), 8.13 (brs: 1H), 8.68 (brs: 1H), 9; , (Mf: 1H), 9.73 (mf: 1H), 10.10 (bs: 1H), (ao20 = + 13.2 +/- 0.7 in 0.5% methanol)] (4RS) -4- (1,2,4-Triazol-1-ylmethyl) -4,5-dihydro-thiazol-2-ylamine dihydrochloride: A solution of 0.3 g of N: [( 4RS) -4- (1,2,4-Triazol-1-ylmethyl) -4,5-dihydro-thiazol-2-yl] -carbamate tert-butyl in 10 cm3 of 4N hydrochloric acid in solution Dioxane is stirred at a temperature in the region of 20 ° C. for 34 hours The reaction mixture is filtered and then washed with diethyl ether (3 × 5 cm 3) and dried in a desiccator to give 0.14 g of (4RS) -4-dihydrochloride. - (1,2,4-triazol-1-ylmethyl) -4,5-dihydro-thiazol-2-ylamine as a white meringue [Mass Spectrof: El m / z = 184 MH + m / z = 183 M4- 'm / z = 114 CiH ^ 4 "m / z = 101 CsHs ^ S4-base peak m / z = 36 DCI HCl m / z = 184 MH +.

Tert -butyl N - [(4RS) -4- (1,2,4-Triazol-1-ylmethyl) -4,5-dihydro-thiazol-2-yl] carbamate: To a solution of 35 g of sodium hydride in 7 cm 3 of dimethyl sulphoxide are added at a temperature in the region of 20 ° C. and under an atmosphere of 0.6 g of 1,2,4-triazole. The mixture is stirred at a temperature in the region of 20 ° C. for 45 minutes and then 1 g of N - [(4RS) -4- (iodomethyl) -4,5-dihydro-thiazol-2-yl] -carbamate is added. ter-butyl. After stirring for 3 hours at a temperature of 60 ° C., 30 cm 3 of a saturated solution of

A ammonium chloride and extracted with 4 times 10 cm of ethyl acetate. The organic phases are washed with 10 cm of saturated sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature of 40 ° C. The residue is chromatographed under an argon pressure of 70 kPa, on a column of silica gel (particle size 40-63μ, diameter 4 cm, height 18 cm), eluting with a mixture of dichloromethane-ethanol (5 / 1 in volumes). The fractions containing the expected product are combined and concentrated under the conditions of the above. 0.34 g of F-butyl N - [(4RS) -4- (1,2,4-triazol-1-ylmethyl) -4,5-dihydro-thiazol-2-yl] carbamate are obtained. in the form of a white foam [Mass spectrum: E m / z = 283 Μ ** m / z = 201C8Hi3N2O2S + m / z = 145 (WW * m / z = 101 C3H5N2S + m / z = 82 CsKdV m / z = 57 Fert -butyl N- [(4RS) -4- (Iodomethyl) -4,5-dihydro-thiazol-2-yl] carbamate: At a suspension of 25.4 g of allylsulfanyl - [( (4-isobutyl-β-butoxycarbonyl) amino] -methylidenecarbamate in 650 cm 3 of dichloromethane is added at a temperature in the region of 20 ° C., 17 g of sodium bicarbonate and then a solution of 24.4 g of iodine dissolved in 850 After 72 hours at a temperature in the region of 20 ° C., 500 cm 3 of water and 500 cm 3 of a saturated solution of sodium bicarbonate are added to the reaction mixture and then the mixture is extracted twice with 1 mm 3 of ethyl acetate. organic phases are washed with a saturated solution of sodium sulphite and then a saturated solution of chlorine of sodium, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature of 50 ° C. The resulting residue is crystallized from ethyl acetate. 20.5 g of tert-butyl N- [(4RS) -4- (iodomethyl) -4,5-dihydro-thiazol-2-yl-carbamate are obtained in the form of a yellow solid (NMR Spectrum). (300MHz, (CD3) 2SO d6, δ in ppm): 1.41 (s: 9H); 2.97 (dd, J = 11.5 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 3H); 4.12 (mt: 1H); 9.89 (mf: 1H) 94 012286

Zer-2-butyl allylsulfanyl - [(Zer-2-butoxycarbonyl) amino] -methylidene carbamate: To a solution of 5 g of 2-allyl-isothiourea hydrochloride in 50 cm 3 of dichloromethane is added a catalytic amount of 4- (dimethylamino) -pyridine and 4.7 cm3 of triethylamine and a solution of 7.1 g of tert-butyldicarbonate previously dissolved in 30 cm3 of dichloromethane is then added dropwise. After 48 hours, the reaction medium is concentrated under reduced pressure (1 μPa) at a temperature in the region of 40 ° C. The residue is chromatographed under an argon pressure of 70 kPa, on a column of silica gel (particle size 40-63μ, diameter 4 cm, height approximately 30 cm), eluting with a mixture of ethyl acetate-cyclohexane. (90/10 in volumes). The fractions containing the expected product are then combined and concentrated under the above conditions. 0.2 g of ZerZ-butyl allylsulfanyl - [(zeri-butoxycarbonyl) amino] -methylidene carbamate are obtained. [Mass spectrum: DCI m / z = 317 mM] = m / z = 261 cmH17O4N2S + m / z = 217C9H17O2N2SxM / z = 161 CsH ^ NsS ^. 2-allyl-isothiourea hydrochloride: To a suspension of 15 g of thiourea in 120 cm 3 of ethanol is added at a temperature of 20 ° C, 16 cm3 of chlorid allyl. After 15 hours at a temperature in the region of 80 ° C., the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 ° C. The solidobtained is taken up with 3 times 100 cm3 of diethyl ether and then filtered. 29 g of 2-allyl-isothiourea hydrochloride are obtained in the form of a white solid (mass spectrum: DCI m / z-lUMH *).

Example 32 (+) - (4R, 5R) -5-Ethyl-4- (pyridin-4-ylmethyl) -4,5-dihydro-thiazol-2-ylamine

A suspension of 4.2 g of N-ZerZ-butyl-N '- [(1R, 2S) -1- (pyridin-4-ylmethyl) -2-hydroxy-butyl] -thiourea in 40 cm 3 of 6N hydrochloric acid is heated to a temperature of about 100 ° C for 20 hours. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50.degree. The residue is chromatographed under pressure

At atmospheric 95 012286, on a column of silica gel (particle size 40-63μ, diameter 3.6 cm, height 24 cm), eluting with a mixture of dichloromethane-methanol (98/2 volumes) and then a mixture of dichloromethane-methanol (97/3 in volumes). The fractions containing the expected product are combined and then concentrated under the above conditions, taken up with 30 cm.sup.3 of dichloromethane, basified with N.sub.2 O.sub.4. The organic phase is dried over magnesium sulphate, filtered and dried under reduced pressure (0.degree. 1 kPa) at a temperature in the region of 40 ° C. 1.4 g of (±) - (4R, 5R) -5-ethyl-4- (pyridin-4-ylmethyl) -4,5-dihydro-thiazol-2-ylamine are obtained in the form of a solid. white melting at 124 ° C [NMR spectrum Ή (30010 ?. MHz, (CD3) 2SO d6, δ in ppm): 0.83 (t, J = 7.5 Hz: 3H); 1.43 (mt: 1H); 1.61 (mt: 1H); 2.70 (AB limit: 2H); 3.40 (mt: 1H); 4.08 (mt: 1H); 6.28 (mf: 2H); 7.29 (broad, J = 5.5 Hz: 2H); 8.45 (d, 5.5 Hz: 2H), (aD20 = +166.9 +/- 2.4 in 0.5% ethanol). N-tert-Butyl-N '- [(1R, 2S) -1- (pyridin-4-ylmethyl) -2-hydroxybutyl) thiourea: To a solution of 3.6 g of dihydrochloride ( 2R, 3S) -2-Amino-1- (pyridin-4-yl) -pentan-3-oline in 60 cm3 of ethanol 4.3 cm3 of triethylamine and then 2.6 cm3 of tert-butyl isothiocyanate are added. The mixture is heated at a temperature of 50 ° C for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C., taken up in 50 cm 3 of water and 100 cm 3 of dichloromethane. The organic phase is washed with 30 cm3 of water, dried over sodium sulfate, filtered and concentrated under the above conditions. 4.3 g of N-tert-butyl-N '- [(1R, 2S) -1- (pyridin-4-ylmethyl) -2-hydroxy-butyl] thiourea are obtained in the form of a thick oil. colorless [NMR spectrum H (300 MHz, (CD3) 2SO d6, δ in ppm): 0.80 (t, J = 7.5 Hz: 3H); from 1.25 to 1.55 (mt: 2H); 1.37 (s: 9H); 2.72 (dd, J = 14 and 9 Hz: 1H); 2.93 (dd, J = 14 and 4.5 Hz: 1H); 3.37 (mt: 1H); 4.60 (mt: 1H); 4.88 (mf: 1H); 7.11 (s: 1H); 7.16 (d, J = 8.5 Hz: 1H); 7.26 (broad d, J - 5.5 Hz: 2H); 8.43 (broad d, J = 5.5 Hz: 2H) j.

(2R, 3S) -2-amino-1- (pyridin-4-yl) -pentan-3-ol dihydrochloride: To a solution of 4 g of N - [(1R, 2S) -2-hydroxy-1- ( teri-butyl pyridin-4-yl-methyl-butyl] -carbamate 50 cm3 of dioxane is added with stirring, at a temperature of 20 ° C, a solution of 50 cm3 of 4N hydrochloric acid in dioxane. This mixture is stirred at a temperature in the region of 20 ° C. for 18 hours and then concentrated under reduced pressure (1 μPa) at a temperature in the region of 60 ° C. 3.6 g of (2R, 3S) -2-amino-1- (pyridin-4-yl) pentan-3-ol dihydrochloride are obtained in the form of a white solid (NMR Spectrum). (300 MHz, (CD3) 2SO d6, δ in ppm): 0.92 (t, J = 7.5 Hz: 3H); from 1.30 to 1.65 (mt: 2H); 3.13 (dd, J = 14 and 9 Hz: 1H); 3.28 (dd, J-14 and 5Hz: 1H); 3.52 (mt: 1H); 3.68 (mt: 1H); 8.11 (broad, J = 6.5 Hz: 2H); 8.25 (mf: 3H); Iron 8.90 (d wide, J = 6.5 Hz: 2H]. N - [(1R, 2S) -2-Hydroxy-1- (pyridin-4-ylmethyl) butyl] carbamate butyl: 9.5 g of a mixture of 85% 15% of the two diastereoisomers of N - [(2RS) -2-hydroxy- (lR) -1- (pyridin-4-yl-methyl) butyl] carbamate ile-butyl is separated on a KROMASIL® 10p C8 column in an acetonitrile-methanol-tetrahydrofuran-water mixture (15/15/5/65 by volume) .The fractions containing the expected product are concentrated under reduced pressure (1 kPa), at a pressure of temperature close to 40 ° C to obtain 4 g of N - [(lR, 2S) -2-hydroxy-1- (pyridin-4-yl-methyl) -butyl] -carbamate deferi-butyl in the form of a solid white [NMR Spectrum Ή (300 MHz, (δb / SOd6, δ in ppm): 0.91 (t, J = 7.5 Hz: 3H), 1.26 (s: 9H); (Mt: 1H), 1.52 (mt: 1H), 2.45 to 2.60 (mt: 1H), 3.02 (dd, J = 14 and 3.5 Hz: 1H); 28 (mt: 1H), 3.53 (mt: 1H), 4.71 (d, J = 6 Hz: 1H), 6.62 (d, J = 9.5 Hz: 1H), 7.20 (mt: 1H); (d wide, J = 5.5Hz: 2H), 8.42 (broad d, J = 5,5 Hz: 2H] N - [(2RS) -2-Hydroxy- (lR) -1- (pyridin-4-yl-methyl) -butyl] -carbamate tert.-butyl: To a solution 10.5 g of N - [(lR) -2-oxobutyl-1- (pyridin-4-yl-methyl)] - carbamate of tol-butyl in 150 cm3 of ethanol, with stirring and at a temperature of 10 ° 2.1 g of sodium borohydride are added and the mixture is stirred at a temperature of 20 ° C. for 18 hours. The reaction medium is concentrated under reduced pressure (1 kPa), at a temperature of 40 ° C, taken up in 100 cm3 of water, extracted with 200 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure (1 kPa), at a temperature of

At 012286 97 about 40 ° C. 9.5 g of a mixture of 85% and 15% of the two diastereoisomers of N - [(2RS) -2-hydroxy- (1R) -1- (pyridin-4-yl-methyl) butyl] -carbamate are obtained. ert-butyl in the form of a yellow gum [NMR spectrum] (300MHz, (CD3) 2SO d6, δ in ppm). We observe a mixture of two diastereoisomers in the proportions 85-15; δ = 0.85 to 0.95 (mt: 3H); from 1.25 to 1.60 (mt: 2H); 1.26 and 1.29 (2 s: 9H in total); from 2.45 to 2.60 (mt: 0.85H); 2.67 (dd, J = 14 and 10 Hz: 0.15H); 2.80 (dd, J = 14 and 4.5 Hz: 0.15H); 3.02 (dd, J14 and 4.5 Hz: 0.85H); from 3.20 to 3.35 (mt: 1H); 3.52 (mt: 0.85H); 3.69 (mt: 0.15H); 416 (d, J = 6Hz: 0.15H); 4.71 (d, J = 6 Hz: 0.85H); 6.41 (d, J = 9.5 Hz: 0.15H); 6.62 (d, J = 9.5 Hz: 0.85H); 7.20 (d, J = 6 Hz: 1.7H); 7.23 (d, J = 6 Hz: 0.3H); from 8.35 to 8.50 (mt: 2H in total)]. N-[(1 R) -2-Oxo-1- (pyridin-4-yl-methyl) butyl] carbamate-butyl carbamate: To a mixture, under an inert atmosphere, of 14 g of N- {2- [N- in the form of 4-methoxy-N- (methyl) amino] -2-oxo (1 R) -1- (pyridin-4-ylmethyl) -ethyl-carbamate of Fe / Y-butyl in 350 cc of tetrahydrofuran, cooled to temperature close to 0 ° C, 50 cm3 of a solution of 3N ethylmagnesium bromide dissolved in diethyl ether is added over 1 hour. After stirring for 48 hours at 0 ° C., water is added to the reaction medium, extracted with dichloromethane and washed with water. The organic phase is dried over sodium sulphate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 10.5 g of tert-butyl N - [(lR) -2-oxo-1- (pyridin-4-yl-methyl) butyl] carbamate are obtained in the form of a yellow-colored oil (M.N. Ή (300 MHz, (δ H 2 SO d 6, δ in ppm): 0.94 (t, J = 7 Hz: 3H), 1.32 (s: 9H), 2.40 to 2.65 (mt: 2H), 2.70 (dd, J = 14 and 10.5 Hz: 1H), 3.06 (dd, J = 14 and 4.5 Hz: 1H), 4.22 (mt: 1H); 26 (broad d, J = 5.5 Hz: 25 2H), 7.44 (broad d, J = 8 Hz: 1H), 8.45 (broad d, J = 5.5 Hz: 2H).

Example 33

(4R) -4- (thien-2-yl-methyl) -4,5-dihydro-thiazol-2-ylamine hydrochloride To a solution of 2.5 g (9.23 mmol) of Boc-D-2- thienylalanine and 1.3 cm3 (9.4 mmol) of triethylamine in 100 cm3 of anhydrous tetrahydrofuran at -20 ° C is added dropwise 0.9 cm3 (9.4 mmol) of ethyl chloroformate. The resulting suspension is stirred at -20 ° C for 1 hour and filtered. The filtrate is cooled to -20 ° C., then a solution of 0.71 g (20.9 mmol) of sodium borohydride in 5 cm 3 of water is added. The reaction mixture is stirred at a temperature of about 20 ° C for 64 hours, then concentrated in vacuo to give a residue which is used directly without purification. A suspension of the product obtained in 20 cm 3 of dioxane is treated with 6 cm 3 of a 4M solution of hydrochloric acid in dioxane, and then stirred at a temperature of 20 ° C for 16 hours. After concentrating the reaction medium under vacuum, 7.7 g of a white solid are obtained which is used directly without purification.

A suspension of the above product (1.0 g), triethylamine (4 cm3, 28.7 mmol) and tert-butylisothiocyanate (0.50 g, 4.3 mmol) in 10 cm3 of ethanol is heated under stirring at a temperature of 50 ° C for 4 hours. After concentration in vacuo, the residue is taken up twice in 50 cm3 of ethyl acetate and then purified by chromatography on a column of silica gel (ethyl acetate / cyclohexane 1: 1 by volume). The fractions containing the expected product are concentrated under reduced pressure to give 255 mg of a white solid which is used directly.

A suspension of the product obtained above (240 mg, 0.88 mmol) is refluxed in 6 cm3 of a 6N hydrochloric acid solution for 8 hours. The reaction mixture is concentrated to dryness under vacuum and the brown residue is triturated in a mixture of ethanol (5 cm 3) and ethyl acetate (3 cm 3), and then filtered. This trituration operation is repeated 3 times, until a clear yellow solution is obtained. After partial concentration, the product crystallizes and is filtered and dried under vacuum to give 64 mg of (4R) -4- (thien-2-yl-methyl) -4,5-dihydro-thiazol-2-ylamine hydrochloride in the form of crystals. light yellow melting at 125-127 ° C [NMR spectrum (300 MHz, (CD3) 2SO d6, δ in ppm): 10.1 (bs, 1H), 9.7 (bs, 1H), 9.3 (bs, 1H), 7.4 (m, 1H), 7.0 (m, 2H), 4.5 (m, 1H), 3.6 (m, 1H), 3.3 (m, 1H), 3.2 (m, 2H).

The pharmaceutical compositions according to the invention consist of a compound of fomajle (I) or an isomer or a tautomer or a salt of such a compound, in the pure form in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active. The drugs according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, it is possible to use tablets, pills, powders (gelatin capsules, cachets) or granules. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under argon. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or coconut oil. paraffin. These compositions may comprise substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.

Sterile compositions for parenteral administration may preferably be aqueous or nonaqueous solutions, suspensions or emulsions. Suitable solvents or carriers are water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be removed at the time of use in sterile water or any other sterile injectable medium. __

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as decaffeinated butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention are particularly useful for the treatment and / or prevention of multiple sclerosis, fetal or global cerebral ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, the disease. Alzheimer's disease, amyotrophic lateral sclerosis, lamigraine, depression, schizophrenia, anxiety, epilepsy, diabetes, atherosclerosis, myocarditis, arthritis, osteoarthritis, asthma, colonirritable, Crohn's disease, peritonitis, gastroesophageal reflux, uveitis, Guillain-Barré syndrome, glomerulo-nephritis, lupus erythematosus, lepsoriasis, the growth of some forms of tumors such as epithelioma, adenocarcinomas or sarcomas, and infections with intracellular or extracellular bacteria, Gram-plus or Gram-less.

The doses depend on the effect sought, the duration of treatment and the route of administration used; they are generally between 1 mg and 100 mg per day orally for an adult with unit doses ranging from 0.5 mg to 50 mg of the active substance. In general, the doctor will determine the appropriate dosage depending on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention:

EXAMPLE A

According to the usual technique, capsules are prepared at 50 mg of active product having the following composition: - Compound of formula (I) ..................... .............................. 50 mg -Cellulose ................ .................................................. ......... 18mg - Lactose ...................................... ....................................... 55 mg - Colloidal silica ...... ............. 1 mg - Sodium carboxymethyl starch ................................ ...... 10 mg - Talc .............. i ......................... ........................................... 10 mg - magnesium stearate. ................................................. 1 mg

EXAMPLE B

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique: - Compound of formula (I) ....................... ............................. 50 mg-Lactose ................. .................................................. .......... 104 mg - Cellulose .................................... ...................................... 40 mg - Polyvidone ........ .................................................. ............. 10 mg - Sodium carboxymethyl starch ................................ ........ 22 mg -Talc ...................................... ............................................. 1θ mg - Stearate magnesium................................................. ... 2 mg - Colloidal Silica .......................................... ....................... 2 mg 102 012286 - Mixture of hydroxymethylcellulose, glycerine, detitane oxide (72-3,5-24,5) qs 1 film-coated tablet, 245 mg

EXAMPLE C

An injectable solution containing 10 mg of active compound having the following composition is prepared: - compound of formula (I) - benzoic acid ............ - benzyl alcohol ....... .. - Sodium Benzoate ...... - 95% Ethanol .............. - Sodium Hydroxide ... - Propylene Glycol ......... ... - Water ................................ .......... 10 mg. ........ 80 mg ........... "0.06 ml .......... 80rog ........... 0, 4 ml ........... 24 mg ........... 1.6 ml qs 4 ml

The present invention also relates to the method of preventing and treating diseases in which abnormal production of nitric oxide (NO) by induction of inducible NO synthase (NOS-2 or iNOS) is involved in the administration of a compound of formula (Γ ) its racemates, enantiomers, diastereoisomers and mixtures thereof, its autotomer and pharmaceutically acceptable salts thereof.

Claims (22)

103 01 2286 CLAIMS 1 - Use of the 2-aminothiazoline derivatives of formula: In which either R1 is a hydrogen atom or an alkyl radical and R2 is unradical alkyl, -alk-NH2, -CH2-R3, -CH2-S-R4 or phenyl substituted with a radical-nitro or -NH-C (= NH ) CH 3, ie R 1 is an alkyl radical and R 2 is a hydrogen atom, R 3 is a cycloalkyl (3-6C), pyridyl, N-pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or phenyl radical substituted by unradical nitro, hydroxy or carboxy, R4 represents a pyridyl radical or N-oxide of pyridyl alk represents an alkylene radical, it being understood that the alkyl and alkylene radicals contain 1 to 6 carbon atoms in straight or branched chain, their racemic, enantiomers , diastereoisomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts for the preparation of pharmaceutical compositions for preventing and treating diseases in which abnormal production of nitric oxide (NO) by NO-synt induction inducible hase (NOS-2) is involved. 012286 104 2 - Use according to claim 1 characterized in that in the formula (Γ) Ri is a hydrogen atom or an alkyl radical and R2 is a radical -alk-NEk, phenylsubstituted by a radical -NH-C (= NH) CH3 , -CH2-R3 and R3 is a pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or phenyl substituted by a nitro or carboxy radical or -CH2-S-R4 and R4 is a pyridyl radical. 3 - Use according to one of claims 1 or 2 characterized in that R2 is a chain -CH2-R3 or -CH2-S-R4, R3 is a 3- or 4-pyridyl radical, 2- or 3-thienyl, 4 or 5-thiazolyl, 1-imidazolyl, 1-triazolyl, 2-pyrazinyl, phenyl or phenylsubstituted in position -3 with a nitro or carboxy radical and R4 is a 4-pyridyl radical. r 4 - Use according to claim 1 characterized in that the compound of formula (I) is chosen from the following compounds: 4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine4- ( 3-nitrobenzyl) -4,5-dihydro-l, 3-thiazol-2-ylamine4-benzyl-5-methyl-4,5-dihydro-l, 3-thiazol-2-ylamine4- (3-thiényhnéthyl) -4 , 5-dihydro-l, 3-thiazol-2-ylamine4- (2-thienylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro- thiazol-4-yl) -phenyl] - (1-imino-ethyl) -amine 4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-carboxybenzyl) -4,5 1,2-Dihydro-1,3-thiazol-2-ylamine 4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4-butyl-4,5-dihydro-1,3-thiazole -2-ylamine-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine 4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-nitrophenyl) - 4,5-Dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine -5-methyl-4- (4-pyridylmethyl) - 4,5-Dihydro-1,3-thiazol-2-ylamine 5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine - (2-Pyrazinylmethyl) -4,5-dihydro-1β-thiazol-2-ylamine 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thia2ol-2-ylmol 4- (4-hydroxybenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-aminopropyl) -4, 4- (4-Pyridylmethyl) 4,5-dihydro-4- (4-pyridylmethyl) -4-dihydro-1,3-thiazol-2-ylamine-4- (1-triazolylmethyl) -455-dihydro-1,3-thia-2-ylamine-N-oxide; racemic, enantiomeric, diastereoisomeric, 1,3-thiazol-2-ylaminelers and mixtures thereof, tautomers and pharmaceutically acceptable salts thereof. - r 5 - Use according to claim 1 characterized in that the compound of formula (I) is chosen from the following compounds: (+ X4R) -4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol 2-ylamine (+) - (4R) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5S) -4-benzyl-5- Methyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2- ylamine (-) - (4R) -4- (3-thiényîméthyl) -4,5 "dihydro-l, 3-thiazol-2-ylamine (4R) -4- (2-thienylmethyl) -4} 5-dihydro- l, 3-thiazol-2-ylamiiie [3- (2-amino-4,5-dihydro-thiazol-4-yl) -phenyl] - (l-imino-ethyl) -amine (+) - (4R) - 4-Benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol-2- ylamine (+) - (4R) -4- (4-aminobutyl) -4,5-dihydro-l, 3-thiazol-2-ylamine (-) - (4S) -4- (3-nitrobenzyl) -4, 5-dihydro-l, 3-thiazol-2-ylamine (-) - (4S, 5S) -4-benzyl-5-methyl-4,5-dihydro-l, 3-thiazol-2-ylamine (-) - (4S) -4- (4-Aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4S, 5R) -4-benzyl-5-methyl-4,5-dihydro-1, 3-Thiaz 2-ylamine (-) - (4R) -4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (5S) -5-methyl-4,5-dihydro- 1,3-thiazol-2-ylamine (-) - (4S) -4-cyclohexylmethyl-455-dihydro-l, 3-thiazol-2-ylamine (+) - (4R) -4-cycîohexyIméthyl-4,5- dihydro-1,3-thiazol-2-ylamine 106 01 2286 4- (3-nitrophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (4- pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -5-methyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3- thiazol-2-ylamine (+) - (4R, 5R) -5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - 4- (5) 4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylam (-) - 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+ ) - (4R) -4- (2-Pyrazinylmethyl) -435-dihydro-1,3-thiazol-2-ylamine (4R) -4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thia2ol -2-ylamine (4S) -4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (4-thiazolyl) methyl) -4 5-Dihydro-1H-3-thiazol-2-ylamine (+) - (4R) -4- (3-aminopropyl) -4-dihydro-1,3-ylazol-2-ylamine (+) - ( 4R) -4- (4-hydroxybenzyl) -4} 5- dihydro-1,3-thiazol-2-ylamine (+) - 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylquinamine N-(4R) -4- (4-Oxide) pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - 4- (1-triazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine their tautomers and their pharmaceutically acceptable salts. 6 - Use according to claim 2 characterized in that the compound of formula (I) is chosen from the following compounds: 4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine4- ( 3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine4-ben2yl-5-methyl-4,5-dihydro-l, 3-thiazol-2-ylamine4- (3-thienylmethyl) -4 , 5-dihydro-l, 3-thiazol-2-ylamine4- (2-thienylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro- thiazol-4-yl) -phenyl] - (l-imino-ethyl) -amine4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine4- (3-carboxybenzyl) -4,5-dihydro- 1,3-Thiazol-2-ylamine-4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol -2-ylamine-5-methyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine h 107 01 2286 5-ethyl-4- (4-pyridylmethyl) -4,5 1-Dihydro-1,3-thiazol-2-ylamine 4- (4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-imidazolylmethyl) -4,5-dihydro-1 3-Thiazol-2-ylamine 4- (2-pyrazinylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (5-thia) zolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine4- (1-triazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine4- (4-pyridylsulfanylmethyl) -4,5 racemic dihydro-1,3-thiazol-2-ylaminelers, enantiomers, diastereoisomers and mixtures thereof, tautomers and pharmaceutically acceptable salts thereof, 7 - Use according to claim 2 characterized in that the compound of formula (I) is chosen from the following compounds: (+) - (4R) -4- (3-pyridylmethyl) -4,5-dihydro-1,3 Thiazol-2-ylamine (+) - (4R) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5S) -4-benyl 5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol -2-ylamine (-) - (4R) -4- (3-thienylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine (4R) -4- (2-thienylmethyl) -4,5 dihydro-l, 3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro-thiazol-4-yl) -phényl3- (l-imino-ethyl) -amine (+) - (4R 4-Benzyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol 2-ylamine (+) - (4R) -4- (4-aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4S) -4- (3-nitrobenzyl) - 4,5-Dihydro-1,5-thiazol-2-ylamine (-) - (4S, 5S) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (- ) - (4S) -4- (4-Aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4S, 5R) -4-benzyl-5-methyl-4,5-dihydro- l, 3-th iazol-2-ylamine (+) - (4R) -4- (4-pyridylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine (+) - (4R, 5R) -5-methyl- 4- (4-pyridylmethyl) -4,5-dihydro-l, 3-thiazol-2-yiamine (+) - (4R, 5R) -5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro -1,3-Thiazol-2-ylamine (+) - 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-H-5-tbiazolylmethyl) -4,5-Dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (2-pyrazinylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4R) 4- (1-Imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4S) -4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2- ylamine 5 (+) - (4R) -4- (4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - 4- (4-pyridylsulfanylmethyl) -4,5-dihydro 1,3-Thiazol-2-ylamine (+) - 4- (1-triazolylmethyl) -4,5-dihydro-1,3-yiazol-2-ylamine, their tautomers and pharmaceutically acceptable salts thereof. 8 - Compounds of formula; R.sub.1 (N) NH.sub.2 in which either R.sup.1 is a hydrogen atom or. an alkyl radical and Rj is unradical alkyl, -alk-NEfe, -CH2-R3, -CH2-S-R4 or phenyl substituted with a radical-nitro or -NH-C (= NH) CH3, or R1 is an alkyl radical and R2 is hydrogen, R3 is cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or phenyl substituted with nitro, hydroxy or carboxy, R4 is pyridyl, alk represents an alkylene radical, their racemates, enantiomers, diastereoisomers and mixtures thereof, tautomers and pharmaceutically acceptable salts thereof. with the exception of the compounds for which R 1 is hexyl or methyl and R 2 is hydrogen or R 1 and R 6 are methyl and the racemic compounds for which R 1 is hydrogen and R 2 is methyl, ethyl or n-propyl, it being understood that the alkyl and alkylene radicals contain 1 to 6 carbon atoms in a straight or branched chain. 9 - Compounds according to claim 8 for which R 1 is a hydrogen atom or an alkyl radical and R 2 is an -alk -NH 2 radical, phenyl substituted with a radical -NH-C (= NH) CH 3, -CH 2 -R 3 for which R 3 is a pyridyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl, phenyl or phenyl radical substituted with a niteo or caiboxy radical or -CH 2 -S-R 4 for which R 4 is a pyridyl radical, it being understood that the alkyl and alkylene radicals contain 1 to 6 ring carbon atoms, their racemic, enantiomeric, diastereoisomeric and mixtures thereof, tautomers and pharmaceutically acceptable salts thereof. 10 - Compounds according to one of claims 8 or 9 characterized in that R3 is unradical R3 is a 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1- triazolyl, 2-pyrazinyl, phenyl or phenyl substituted in the 3-position by a nitro or carboxy radical and R4 is a 4-pyridyl radical. 11 - Compounds according to claim 8 chosen from the following: 4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine4- (3-nitrobenzyl) -4,5-dihydro-1, 3-thiazol-2-ylamine4-benzyl-5-methyl-4,5-dihydro-l, 3-thiazol-2-ylamine4- (3-thienylmethyl) -4,5-dihydro-l, 3-thiazol-2- ylamine4- (2-thiényîméthyl) -4,5-dihydro-l, 3-thiazol-2-ylamine [3- (2-amino-4,5-dihydro-thiazol-4-yl) -phenyl] - (l- imino-ethyl) -amine-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine 4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4-Aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine-methyl-4 (4-Pyridylmethyl) -4-dihydro-1,3-thiazol-2-ylamine 5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4 4 - (4-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-imidazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (2- 4-yiazanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (5-Thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (1-triazolyl) ethyl) -4,5-dihydro-1,3-thiazol-2-ylamine 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine their racemates, enantiomers, diastereoisomers and mixtures thereof, their tautomers and their pharmaceutically acceptable salts. 12 - Compounds according to claim 8 selected from the following ·: (+) - (4R) -4- (3-pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine. (+) - (4R) -4- (3-Nitrobenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5S) -4-ben2yl-5-methyl-4 5-Dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4R) -4- (3-Thienylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (4R) -4- (2-thienylmethyl) -4,5-dihydro-1,3- thiazol-2-ylamine ?? [3- (2-Amino-4,5-dihydro-thiazol-4-yl) -phenyl] - (1-imino-ethyl) -amine (+) - (4R) -4-ben2yl-4,5-dihydro -1,3-thiazol-2-ylamine (+) - (4R) -4- (3-carboxybenzyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4 - (4-Aminobutyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4S) -4- (3-nitrobenzyl) -4,5-dihydro-1,3-thiazol 2-ylamine (-) - (4S, 5S) -4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (-) - (4S) -4- (4-aminobutyl) ) -4,5-Dihydro-1,3-thiazol-2-ylamine (4S, 5R) -4-benyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R) -4- (4-Pyridylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -5-methyl-4- (4-pyridylmethyl) -4 5-Dihydro-1,3-thiazol-2-ylamine (+) - (4R, 5R) -5-ethyl-4- (4-pyridylmethyl) -4,5-dihydro-1,3-thiazol -2-ylamine (+) - 4- (5-thiazolylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (-) - 4- (5-thiazolylmethyl) -4,5'dihydro-1 3-Thiazol-2-ylamine (+) - (4R) -4- (2-pyrazinylmethyl) -4,5-dihydro-1,3-tbiazol-2-ylamine (4R) -4- (1-imidazolylmethyl) ) -4,5-Dihydro-1,3-thiazol-2-ylaniine (4S) -4- (1-imidazolyl) thyl) -4,5-dihydro-l, 3-thiazol-2-ylaniine (+) - (4R) -4- (4-thiazolylmethyl) -4,5-dihydro-l, 3-thiazol-2-ylamine ( +) - 4- (4-pyridylsulfanylmethyl) -4,5-dihydro-1,3-thiazol-2-ylamine (+) - 4- (1-triazolylmethyl) -4,5-dihydro-1,3-thiazole And their tautomers as well as their pharmaceutically acceptable salts. 13 - Pharmaceutical compositions containing as active ingredient at least one compound of formula In which either R1 is a hydrogen atom or an alkyl radical and R2 is unradical alkyl, -alk-NH2, -CH2-R3, -CH2-S-R4 or phenyl substituted with a radical-nitro or -NH-C (= NH) CH 3 or R 1 is alkyl and R 2 is hydrogen, R 3 is cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl, phenyl or radical substituted phenyl nitro, hydroxycarboxy, R4 represents a pyridyl radical, alk represents an alkylene radical, 0) 2286 112 their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts, with the exception of the racemic compounds for which R 1 is a methyl radical and R 2 is a hydrogen atom or R 1 is hydrogen and R 2 is methyl, ethyl or n-propyl, it being understood that the alkyl and alkylene radicals contain 1 to 6 carbon atoms in a straight or branched chain 14 - Process for the preparation of the compounds of formula (I) according to claim 810 characterized in that one cyclizes a derivative of formula: OH - NH - CS - NH - C (CH 3) 3 (H) in which R 1 and R 2 have the same meanings as in claim 8, isolele product and optionally converted into pharmaceutically acceptable salt. 15 - Process for the preparation of the compounds of formula (I) according to claim 8 for which R2 is a phenyl radical substituted with a -NH-C (= NH) CH3 radical, characterized in that a derivative of formula: with benzylethanimidothioate hydrochloride, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 01 2286 113 16 - Process for the preparation of the compounds of formula (Ί) according to claim 8 for which Ra is a radical -CH2-R3 in which R3 is a 1-imidazolyl or 1- (1,2,4-triazolyl) radical, characterized in that the imidazole or 1,2,4-triazole is reacted with a derivative of the formula: (IV) wherein R 1 has the same meanings as in claim 8, X is an atom of halogen or a tosyl radical, Ra and Rb are hydrogen atoms or groups protecting the amine function, followed optionally by deprotection, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 17 - Process for the preparation of the compounds of formula (T) according to claim 8 for which R2 is a -CH2-S-R4 radical, characterized in that a compound of formula: In which R 1 has the same meanings as in claim 8, X is an atom of halogen or a tosyl radical, Ra and Rb are hydrogen atoms or groups protecting the amine function, on a derivative of formula HS-R4 in which R4 has the same meaning as in claim 8, optionally followed by deprotection of the amine function, isolates the product and optionally converts it into a pharmaceutically acceptable salt. Οι2286 114 18 τ Compounds of formula: 19 - Process for the preparation of the compounds of formula (H) as defined in claim 14 and in which R1 is a hydrogen atom, characterized in that a compound of formula (IIa) is subjected to FL-CH- NHRa (IIa) wherein R2 is as defined in claim 1 and Ra is either a hydrogen atom or a protecting group of the amine formation such as CO2 tbu with the action of a reducing agent to obtain the compound of formula (Rb) R "- CH-NHRa (Hb) • CH9OH 10 2 which is subjected to the action of a deprotection agent in order to obtain a compound of the formula (Ile) Rf-CH-NH2 (Hc) I CH 2 OH which is subjected to the action of tert-butylthiocyanate to obtain a compound of formula (II) ch2oh corresponding to the compound of formula (Π) with Ri representing a hydrogen atom. As intermediate compounds, the compounds of formulas (bb), (Hc) or (Hd) as defined in claim 19. By way of intermediate compounds, the compounds of formula (Hd) as defined in claim 19. As intermediate compounds, the compounds of formulas (Kb), (IIc) or (IId) as defined in Claim 19 and in which R 2 represents a 4-pyridylmethyl group with the exception of 4-ethylamine. pyridinepropanol. As intermediate compounds, the compound of formula (Hd) as defined in claim 19 and wherein R2 represents a 4-pyridylmethyl group.